Clinical trial NCT01351350
Conditions: Advanced Solid Malignancies Hematologic Malignancies
Keywords: Solid tumor, mTORC1/2 inhibitors, HER2
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2011-02-28; Completion date: 2017-09-15
Enrollment: 68 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase I, open label, dose escalation study of oral administration of MLN0128 in combination with paclitaxel, with/without trastuzumab, in participants with advanced solid malignancies.

Detailed description:
This is a Phase I, open-label study consisting of a dose escalation phase in advanced solid malignancies to determine the maximum tolerated dose (MTD) of oral administration of MLN0128 in 1 or more dosing schedules, combined with paclitaxel on Days 1, 8 and 15 of each cycle, followed by an expansion phase for further safety and preliminary efficacy.

Once the MTD is determined for each of the dosing schedules evaluated, a dose and schedule will be selected for the expansion phase, which may enroll participants into 2 arms in parallel:

* Arm A will consist of HER2- unknown cancer participants receiving MLN0128+paclitaxel
* Arm B will consist of HER2+ cancer participants receiving MLN0128+paclitaxel plus weekly trastuzumab

Arms: arm 1: MLN0128 and paclitaxel (MLN0128P): MLN0128 30 mg, capsule, orally, once weekly (QW) + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 2: MLN0128 40 mg, capsule, orally, once a week (QW) + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 3: MLN0128 6 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 4: MLN0128 7 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 5: MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 6: MLN0128 9 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 7: MLN0128 10 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 8: MLN0128 7 mg, capsule, orally, once daily 5 days on/2 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. arm 9: MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in human epidermal growth factor receptor 2 negative (HER-) cancer participants until disease progression or unacceptable toxicity for up to 1 year in the Expansion Phase. arm 10: MLN0128 + paclitaxel + trastuzumab (MLN0128PH): MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m\^2, 1 hour infusion, on Days 1, 8 and 15 plus trastuzumab 4 mg/kg loading dose on Day 1 followed by 2 mg/kg, intravenous each week of a 4-week cycle in HER+ cancer participants until disease progression or unacceptable toxicity for up to 1 year in the Expansion Phase.
Interventions: intervention 1: MLN0128 intervention 2: paclitaxel intervention 3: trastuzumab
Intervention descriptions: intervention 1: MLN0128 capsules intervention 2: paclitaxel intravenous infusion intervention 3: trastuzumab intravenous infusion

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Phase I, Open Label, Dose Escalation Study of Oral Administration of INK128 in 
Combination with Paclitaxel, with/without Trastuzumab, in Subjects with Advanced Solid 
Malignancies
NCT Number: 
Protocol Approve Date: March 5, 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 or company confidential information. 
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.


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CCI


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
5
in combination with paclitaxel on Days 1, 8, and 15 of each cycle (MLN0128P), followed by an 
expansion phase at the MLN0128P MTD (MTDMLN0128P) ± trastuzumab for further safety and 
preliminary efficacy.  A cycle will be defined as 4 weeks.
Once the MTDMLN0128P is determined for each of the dosing schedules evaluated, an additional 6 
subjects may be enrolled at the MTDMLN0128P for further safety and PK evaluation.  A dose and 
schedule will be selected for the expansion phase, which may enroll subjects into 2 arms, A and B, in 
parallel:

Arm A will consist of HER2- cancer subjects receiving MLN0128P at the MTDMLN0128P

Arm B will consist of HER2+ cancer subjects receiving MLN0128P at the MTDMLN0128P plus 
weekly trastuzumab (MLN0128PH)
NUMBER OF SUBJECTS PLANNED:
Cohorts of 3 to 6 subjects with advanced solid malignancies will be enrolled at each MLN0128 dose 
level evaluated in combination with paclitaxel in 4-week cycles; the exact number of total subjects 
enrolled will depend on the number of dose levels assessed and the toxicities observed.  During dose 
escalation, subjects who discontinue treatment before completing ≥ 75% of planned MLN0128 doses 
in Cycle 1 for reasons other than study drug-related toxicity will be replaced.  Approximately 15 to 20 
safety-evaluable subjects may be enrolled into each arm of the expansion phase.  It is estimated that 
approximately 95 subjects may be enrolled in the entire study.
DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:
Individuals eligible to participate in this study must meet all of the following Inclusion Criteria:
1.
Age ≥ 18 years, including males and females;
2.
Subjects must have locally advanced or metastatic solid tumors with the exception of primary 
brain tumor, and have failed or are not eligible for standard of care therapy. Subjects with a 
history of brain metastasis are eligible for the study as long as they meet all the following criteria: 
their brain metastases have been treated, they have no evidence of progression or hemorrhage after 
treatment, have been off dexamethasone for 4 weeks prior to first study drug administration, and 
they have no ongoing requirement for dexamethasone or anti-epileptic drugs;
3.
For Arm A of the expansion phase only, subjects with advanced bladder cancer or endometrial 
cancer will be enrolled and must have received at least 1, but no more than 2 prior lines of 
systemic therapy, including adjuvant or hormonal therapy;
4.
For Arm B of the expansion phase only, HER2+ cancer is defined as a pathologic diagnosis of 
cancer which is 3+ by immunohistochemistry (IHC) for HER2 or positive for HER2 gene 
amplification by fluorescence in situ hybridization (FISH) and subjects must have received at least 
1, but no more than 4 prior lines of systemic cytotoxic chemotherapy, excluding adjuvant, 
hormonal, or targeted therapy;
5.
Subjects must have received no more than 4 prior lines of systemic cytotoxic chemotherapy for 
advanced or metastatic disease;
6.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1;
7.
Subjects must have adequate organ function, including the following:
a. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x109/L; 
platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL without transfusion in the last 2 weeks;
b. Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases (aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine 
aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 2.5 x ULN (<5 x 
ULN if liver metastases are present);


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
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c. Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min (Cockroft 
- Gault formula);
d. Metabolic: fasting serum glucose ≤130 mg/dL, and fasting triglycerides ≤ 300 mg/dL;
8.
Left ventricular ejection fraction (LVEF) ≥ 5 absolute percentage points below institutional 
standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional normal is 
50%, subject’s LVEF may be as low as 45% to be eligible for the study);
9.
For women of child-bearing potential, negative serum pregnancy test within 14 days prior to the 
first study drug administration and use of physician-approved method of birth control from 
30 days prior to the first study drug administration to 90 days following the last study drug 
administration;
10. Male subjects must be surgically sterile or must agree to use physician-approved contraception 
during the study and for 90 days following the last study drug administration;
11. Ability to swallow oral medications;
12. Ability to understand and willingness to sign informed consent form prior to initiation of any 
study procedures.
Individuals who meet any of the following Exclusion Criteria will not be eligible to participate in the 
study:
1.
Diagnosis of primary brain tumor;
2.
Have received prior cancer or other investigational therapy within 2 weeks prior to the first 
administration of study drug.  For prior therapies with a half life longer than 3 days, the interval 
must be at least 28 days prior to the first administration of study drug and the subject must have  
documented disease progression.  For prior trastuzumab therapy in subjects who enroll in Arm B 
of the expansion phase, the interval since last prior trastuzumab dose must be at least 7 days;
3.
Have initiated hematopoietic growth factors within one week prior to the first administration of 
study drug; subjects already receiving hematopoietic growth factors on a chronic basis for ≥ 4 
weeks are eligible;
4.
Chronic systemic corticosteroid (except inhalers) use within one week prior to the first 
administration of study drug.  Premedication with dexamethasone prior to paclitaxel 
administration in this study is allowed;
5.
Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an 
unknown reason that may alter the absorption of MLN0128;
6.
Poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with a history of transient 
glucose intolerance due to corticosteroid administration are allowed in this study if all other 
inclusion/exclusion criteria are met;
7.
Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central 
nervous system (CNS) disease, active infection, or any other condition that could compromise the 
subject’s participation in the study;
8.
Known human immunodeficiency virus (HIV) infection;
9.
Pregnancy (positive serum or urine pregnancy test) or breast feeding;
10. Any history of unstable angina, myocardial infarction, New York Heart Association (NYHA) 
Class III or IV heart failure (See Appendix C), and/or pulmonary hypertension;
11. Significant active cardiovascular disease including:
o Uncontrolled high blood pressure (ie, systolic blood pressure >180 mm Hg, diastolic blood 


MLN0128
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pressure > 95 mm Hg)
o Grade 3 or higher valvular disease
o Grade 3 or higher atrial fibrillation
o Grade 3 or higher bradycardia
o Endocarditis
o Pulmonary embolism
o Recent cerebrovascular accident within 6 months prior to enrollment
12. A requirement for inotropic support or serious uncontrolled cardiac arrhythmia (including atrial 
flutter/fibrillation) within 1 year prior to screening
13. A pacemaker or implantable cardiac defibrillator
14. Baseline prolongation of the rate-corrected QT interval (QTc) (eg, repeated demonstration of 
QTc interval > 480 milliseconds) (See Section 7.8.2.2).
15. History of congenital long QT syndrome, ventricular fibrillation, ventricular tachycardia or 
torsades de pointes
Other Considerations for Exclusion:
Patients taking strong CYP3A4, and CYP2C19 inhibitors and/or inducers should be considered with 
caution.  Alternative treatments that are less likely to affect MLN0128 metabolism, if available, should 
be considered.  If a patient requires treatment with one or more of the strong CYP3A4, and CYP2C19 
inhibitors and/or inducers, the medical monitor should be consulted.  Examples of the strong CYP3A4 
and CYP2C19 inhibitors and inducers include (see Appendix B):
Strong inhibitors:
CYP3A4: ketoconazole, itraconazole, ritonavir, mibefradil, indinavir, clarithromycin
CYP2C19: fluconazole, fluvoxamine, omeprazole, ticlopidine
Strong inducers:
CYP3A4: rifampin (also a moderate CYP2C19 inducer), phenytoin, carbamazepine, St. 
John’s wort
Patients should not consume food or beverages containing the fruit or juice from grapefruits, 
pomegranates, star fruit, papayas, or Seville oranges within 7 days before first dose of study 
drug.
INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:
MLN0128 (formerly, INK128) is a mammalian target of rapamycin (mTOR) complex 1 (mTORC1) 
and mTOR complex 2 (mTORC2) inhibitor currently under clinical investigation.  Paclitaxel is an 
antimicrotubule agent approved by the Federal Drug Administration (FDA) and European Medicines 
Agency (EMA) for treatment of breast, ovarian, and non-small cell lung cancers.  Trastuzumab is a 
recombinant DNA-derived humanized monoclonal antibody that binds to the extracellular domain of 
the human epidermal growth factor receptor 2 protein (HER2) and is approved by the FDA and EMA 
for the treatment of breast and gastric cancer with HER2 overexpression.  The combinations of 
MLN0128 and paclitaxel (MLN0128P) during the dose escalation and expansion phase, and 
MLN0128P plus trastuzumab (MLN0128PH) in Arm B of the expansion phase are considered 
investigational.
MLN0128 will be supplied in tamper-resistant high density polyethylene bottles as capsules containing 
1 mg, 3 mg, or 5 mg dose strengths, which the pharmacist will use to make up the appropriate dose for 
each dose cohort.  On each clinic day, the subject should return any unused study drug.  A full 
accountability of these supplies by the site staff and the sponsor’s designated Clinical Research 


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
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Associate (CRA) should be conducted before they are destroyed.
Cycles of MLN0128P and MLN0128PH are repeated every 4 weeks (28 days).
MLN0128 will be initially administered orally on a schedule consisting of daily administration of 
MLN0128 QDx3d QW on a 4-week cycle.  On days when weekly paclitaxel is administered (Days 1, 
8 [±1 day], and 15 [±1 day] of every 28-day cycle), MLN0128 will be administered in the clinic within 
30 minutes of the completion of paclitaxel infusion.  On Day 22 (±1 day) when paclitaxel is not 
administered, MLN0128 will be administered alone for subjects receiving MLN0128P and within 30 
minutes of the completion of trastuzumab for subjects receiving MLN0128PH.  The starting dose of 
MLN0128 is 6 mg daily for the first 3 days (Days 1-3) of each week.  If a DLT is observed in 2 or 
more subjects in a cohort of 3 to 6 subjects treated with the starting dose of 6 mg, a new cohort of 3 to 
6 subjects will be enrolled at either 4 mg or an intermediate dose level between 4 mg and 6 mg.  With 
implementation of Amendment 1, alternate dosing schedules (such as QDx5d QW) of MLN0128
administration in combination with paclitaxel may be evaluated to optimize tolerability and exposure 
of the combination.  For the intermittent dosing schedules (such as QDx3d QW or QDx5d QW), in 
subsequent dose escalation cohorts, MLN0128 will be administered at approximately 24 hours 
following completion of paclitaxel infusion.  For example, on the QDx3d QW dose schedule, 
paclitaxel will be administered on Days 1, 8 [±1 day], and 15 [±1 day] and MLN0128 will be 
administered on Days 2-4, 9-11, 16-18, and 22-24 of every 4-week cycle.  Likewise, on the QDx5d 
QW dose schedule, paclitaxel will be administered on Days 1, 8 [±1 day], and 15 [±1 day] and 
MLN0128 will be administered on Days 2-6, 9-13, 16-20, and 22-26 of every 4-week cycle.
Dose escalation will be according to a modified Fibonacci schema.  For example, a starting dose of 
6 mg may be escalated in successive cohorts to 8 mg, 10 mg, etc. or an intermediate dose between 2 
planned doses may be evaluated.  The level of dose escalation or a decision to go to an intermediate 
dose or a lower dose will be determined after discussion between the participating investigators and 
Millennium’s medical monitor before dose escalation, but will not exceed the planned next escalated 
dose according to the modified Fibonacci schema.
Paclitaxel 80 mg/m2 will be given intravenously (IV) weekly on Days 1, 8 (±1 day), and 15 (±1 day) of 
every 28-day cycle in combination with MLN0128.  Paclitaxel will be administered according to the 
FDA label (Taxol® package insert) and institution’s standard clinical practice.
HER2+ cancer subjects enrolled in Arm B of the expansion cohort will receive MLN0128P at the 
MTDMLN0128P in addition to weekly trastuzumab (MLN0128PH).  A 4 mg/kg loading dose of 
trastuzumab will be given intravenously on Cycle 1 Day 1, followed by 2 mg/kg IV weekly thereafter.  
For subjects entering expansion Arm B already receiving trastuzumab, the C1D1 dose will be 2 mg/kg 
if the last trastuzumab dose had been administered within 28 days.  If the last trastuzumab dose was 
administered >28 days before C1D1, then the 4 mg/kg loading dose will be administered.
Trastuzumab will be administered intravenously on Days 1, 8 (±1 day), 15 (±1 day), and 22 (±1 day) 
of every 28-day cycle prior to paclitaxel administration on Days 1, 8 (±1 day), and 15 (±1 day) and 
prior to MLN0128 administration on Day 22 (± 1day) according to the FDA label (Herceptin® package 
insert) and institution’s standard clinical practice.
DURATION OF TREATMENT:
In the absence of unacceptable treatment-related toxicity or disease progression, subjects may receive 
the combination treatment MLN0128P or MLN0128PH (expansion phase in Arm B only) treatment 
for up to 1 year at the discretion of the Investigator and beyond 1 year with the agreement of the 
Investigator and the Sponsor.  Subjects will remain on study as long as they continue to receive 
MLN0128, paclitaxel, or trastuzumab without additional anti-cancer therapies.


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
9
REFERENCE THERAPY(IES), DOSE, ROUTE AND REGIMEN:
None.
CRITERIA FOR EVALUATION:
Safety:
Safety will be assessed by periodic physical examinations, 12-lead electrocardiograms (ECGs), 
echocardiogram/multi-gated acquisition scan (MUGA), clinical laboratory assessments, in-home 
monitoring of glucose levels with a glucometer and monitoring of adverse events (AEs).  Adverse 
events will be graded using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. Site teleconferences between the sponsor and all participating 
sites will be held approximately every 1 to 2 weeks during the dose escalation phase to discuss any 
suspected AEs/DLTs that have occurred in subjects within each cohort.  Participating Investigators and 
the Sponsor’s Medical Monitor will review study drug-related toxicities from the current cohort during 
the site teleconferences before escalating to the next dose.
Pharmacokinetics:
The PK profile will be assessed by determining the plasma levels of MLN0128 and paclitaxel at 
intervals throughout the study.  For subjects enrolled prior to Amendment 1, blood samples for PK 
profile will only be collected in subjects during the dose escalation phase at the following time points:
1.
Cycle 1 Day 1 (C1D1): predose
2.
Cycle 1, Day 1 (C1D1): immediately at the end of paclitaxel infusion (EOPI and pre-MLN0128
dose), and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 min), and 6 
hours (± 30 min) post-MLN0128 C1D1 dose, and
3.
Cycle 1, Day 2 (C1D2 = 24 ±2 hours post-MLN0128 C1D1 dose): pre-MLN0128 dose, and
4.
Cycle 2 Day 1 (C2D1): predose
5.
Cycle 2, Day 1 (C2D1): immediately at EOPI and pre-MLN0128 dose, and at 0.5 hour 
(±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 min), and 6 hours (± 30 min) 
post-MLN0128 C2D1 dose.
For subjects enrolled following implementation of Amendment 1, blood samples for PK profile will 
only be collected during the dose escalation phase at the following time points:
1.
Cycle 1 Day 1 (C1D1): predose
2.
C1D1: immediately at EOPI, and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 
4 hours (± 30 min), and 6 hours (± 30 min) post-paclitaxel C1D1 dose, and
3.
Cycle 1, Day 2 (C1D2 = 24 ±2 hours post-paclitaxel C1D1 dose): pre-MLN0128 dose, and at 0.5 
hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 min), and 6 hours (± 30 min) 
post-MLN0128 C1D2 dose, and
4.
Cycle 2 Day 1 (C2D1): predose
5.
C2D1: immediately at EOPI, and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 
hours (± 30 min), and 6 hours (± 30 min) post-paclitaxel C2D1 dose, and
6.
Cycle 2, Day 2 (C2D2 = 24 ±2 hours post-paclitaxel C2D1 dose): pre-MLN0128 dose, and at 0.5 
hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 min), and 6 hours (± 30 min) 
post-MLN0128 C2D2 dose.
Pharmacodynamics:
Pharmacodynamic assessment will be made by evaluation of various biomarker levels in tumor biopsy 
samples pre- and post-treatment during both the dose escalation and expansion phases of the study. 


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MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
11
Efficacy Analyses:
Efficacy analyses will be conducted for subjects with measurable disease at study entry as defined by 
RECIST (version 1.1) with adequate baseline and post-baseline disease assessments.  The efficacy 
results will be presented by individual subject and dose cohort, and by tumor histology.  The number 
and percentage of subjects experiencing objective response (complete response and partial response) 
will be summarized.  The duration of objective response will be summarized descriptively using the 
Kaplan-Meier method.
Pharmacokinetic Analyses:
PK parameters, including area under the curve (AUC), maximum concentration (Cmax), minimum 
concentration (Cmin), time of maximum concentration (Tmax), and half life (t1/2) for MLN0128 and 
paclitaxel will be determined. The additional intravenous PK parameters, clearance (CL), and volume 
of distribution (Vss) will be estimated for paclitaxel. Comparisons across dose levels will be made to 
assess proportionality. In addition, comparison between single dose and multi-dose PK parameters 
will be made for assessment of steady-state drug accumulation.


MLN0128
Clinical Study Protocol INK128-003 Amendment 6
Confidential
12
2.1
Schedule of Events
Table 2.1   
Schedule of Events – Cycle 1
Assessments
Screening /Baseline
Treatment 
Termination Visit20
Within 
28 days 
Within 
14 days
Day 1
(prior to dose)
Day 1 
Day 221
Day 8
(±1 day)
Day 15
(± 1 day)
Day 22
(± 1 day)
Informed Consent and HIPAA
X
Medical History
X
Vital signs, Height1, Weight and ECOG PS
X1
X22
X
X
X
X
Complete Physical Examination2
X
X22
X
X
X
X
12-lead ECG3
X
X22
X23
X23
X
X
X
X
ECHO/MUGA
X
X
Hematology4
X
X
X
X
X
X
Chemistry5
X
X
X
X
X
X
Coagulation (PT/INR, PTT)
X
X
X
Fasting Serum Glucose6
X
X22
X6
X
X
X
X
Glycosylated Hemoglobin (HbA1c)
X
X
Fasting Lipid Profile7
X
X
Urinalysis8
X
X22
X
X
X
X
Serum or Urine Pregnancy Test9
X
X22
PK Timing10
X
X
X
Tumor Biopsies for PD Evaluation11
X
X
X
X
Archival Tumor Tissue12
X
Radiographic Tumor Evaluation and Tumor 
Markers13
X
X24
In-Home Daily Fasting Glucose 
Monitoring14
X
X
X
X
AE Monitoring15
X
X
X
X
X
X
X
Concomitant Medications16
X
X
X
X
X
X
X
X
X
MLN0128 Treatment17
X17
X17
X17
X17
X17
Paclitaxel Administration18
X
X
X
Trastuzumab Administration19 – Only in 
Arm B of Expansion Phase
X
X
X
X


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
13
1.
Height is only needed at Screening/Baseline.
2.
Complete physical examination will be performed at Screening/Baseline, C1D1 and at the Termination visit.  Symptom directed physical examination will be done on C1D8 
(±1 day), C1D15 (±1 day) and C1D22 (±1 day).
3.
All scheduled ECGs should be performed after the patient has rested quietly for at least 5 minutes in a supine position. When the timing of ECG assessments coincides with a 
blood collection, the ECG should be obtained prior to the nominal time of the blood collection.  In some cases, it may be appropriate to repeat an abnormal ECG to rule out 
improper lead placement as contributing to the ECG abnormality.
4.
Complete blood count (CBC) includes white blood cell count (WBC) with differential, hemoglobin (Hgb), hematocrit (Hct), and platelet count.  CBC results performed pre-
dose on Days 1, 8, 15 and 22 of Cycle 1 must be available and reviewed by the investigator prior to trastuzumab, paclitaxel, or MLN0128 dosing.
5.
Full chemistry panel includes Chem 7 (sodium [Na], potassium [K] chloride [Cl], bicarbonate [CO2], blood urea nitrogen [BUN], creatinine [Cr], glucose), liver function tests 
(LFTs - ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin), lactate dehydrogenase (LDH), total protein, calcium, phosphate, and magnesium.  Chem 7 and LFT 
results performed pre-dose on Days 1, 8, 15, and 22 of Cycle 1 must be available and reviewed by the investigator prior to trastuzumab, paclitaxel, or MLN0128 dosing.  
Electrolyte levels should be corrected as needed before MLN0128 dosing, or before paclitaxel or trastuzumab dosing on days when paclitaxel or trastuzumab are administered 
24 hours before MLN0128 dosing.
6.
Fasting serum glucose will be measured prior to dexamethasone premedication for subjects receiving MLN0128P or prior to trastuzumab infusion for subjects receiving 
MLN0128PH on Cycle 1 Day 1 (C1D1), pre-MLN0128 dose on C1D2 when the pre-MLN0128 dose PK sample is drawn (dose escalation phase only), and before 
dexamethasone premedication (prior to MLN0128 on C1D22 when paclitaxel is not administered) for subjects receiving MLN0128P or prior to trastuzumab infusion for 
subjects receiving MLN0128PH on C1D8 (±1 day), C1D15 (±1 day), C1D22 (±1 day) and at the Termination visit.  Additionally, upon implementation of Amendment 1 and 
under Amendment 2, fasting blood glucose will be measured at 1 hour post-MLN0128 dosing on C1D2 when PK samples are drawn in the dose escalation phase only. 
7.
Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides.
8.
Urinalysis will include macroscopic assessment of the amount of protein, glucose, white blood cells and blood if they are present (levels should be recorded if available) and 
microscopic analysis should be performed if an abnormality is noted.  Microscopic urinalysis will also be performed along with a 12-hour urine collection and spot urine 
electrolytes, protein and creatinine, and serum chemistry at any time when the serum creatinine is ≥ Grade 1 according to NCI CTCAE version 4.0.
9.
Only for female subjects with child-bearing potential.  Serum pregnancy test will be done at Screening/Baseline.  Either serum or urine pregnancy test will be done on C1D1.
10. Plasma PK samples will be obtained for subjects in the dose escalation phase prior to determination of the MLN0128P MTD at the following time points under the original 
protocol: pre-dose, immediately at the end of paclitaxel infusion (EOPI and pre-MLN0128 dose), and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours 
(± 30 min), 6 hours (± 30 min), and 24 ±2 hours post-MLN0128 dose on C1D1.  The PK sample draw on C1D2 (24 hours post-MLN0128 dosing) will be obtained before 
C1D2 MLN0128 dosing.  Upon implementation of Amendment 1, plasma PK samples will be obtained for subjects in the dose escalation phase of the study at the following 
time points: on C1D1, pre-dose, immediately at EOPI, and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (±30 min), 4 hours (±30 min), and 6 hours (±30 min) 
post-paclitaxel infusion completion; and on C1D2, pre-MLN0128 dose, and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (±30 min), 4 hours (±30 min), and 6 hours 
(±30 min) post-MLN0128 C1D2 dose.
11. Fresh tumor tissue biopsies will be taken from subjects who have accessible tumor tissues based on the Investigator’s judgment and who have signed the consent for tumor 
biopsy.  Fresh tumor tissue collections should coincide with the collection of PK samples at 3 hours ± 1 hour post-MLN0128 dose.
12. Every effort should be made for all subjects who have available archival tumor tissues to collect either paraffin blocks or a minimum of 10 unstained slides of archival tumor 
tissue for assessment of predictive/prognostic markers.  Archival tumor tissues can be collected after the subject begins study drug treatment, if extra time is needed to locate 
the specimens.
13. Baseline CT (with contrast)/MRI of chest, abdomen and pelvis and relevant tumor markers (eg, cancer antigen [CA]125, prostate-specific antigen [PSA], CA19-9, CA27.29, 
CA15.3, and carcinoembryonic antigen [CEA]) must be obtained within 4 weeks prior to the first dose.  A confirmatory scan should be performed at approximately 4 weeks 
from the previous scan for all subjects with an objective response of ≥ PR.  The same method (CT with contrast or MRI) must be used throughout the study.


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
14
14. Subjects will be given a glucometer on C1D2 to monitor daily fasting whole blood glucose level at home and will be instructed to notify the study doctor when the fasting
glucose is abnormal.  The early detection and treatment of hyperglycemia has been key in managing this drug-related adverse event effectively in previous human studies with 
MLN0128.  Each institution should decide an abnormal fasting glucose level (ie, ≥ 140 mg/dL) where the treatment and close monitoring of hyperglycemia might be required.
15. Adverse events will be collected after administration of the first dose of MLN0128, paclitaxel or trastuzumab through 30 days following the last dose of study drug.
16. Concomitant medications will be collected from 30 days prior to the first dose of study drug (MLN0128, paclitaxel or trastuzumab) until termination of the study.
17. Prior to Amendment 1, MLN0128 was initially to be given orally on a schedule consisting of daily administration of MLN0128 for 3 days on, 4 days off repeated each week 
(QDx3d QW of a 4-week cycle).  On days when weekly paclitaxel is administered (Days 1, 8 [±1 day], and 15 [±1 day] of every 28-day cycle), MLN0128 was to be 
administered in the clinic to the subject within 30 minutes of the completion of paclitaxel infusion.  On Day 22 (±1 day) when paclitaxel is not administered, MLN0128 was 
to be administered alone for subjects receiving MLN0128P and within 30 minutes of the completion of trastuzumab for subjects receiving MLN0128PH.  The starting dose of 
MLN0128 is 6 mg daily for the first 3 days (Days 1-3) of each week.  Upon implementation of Amendment 1 in subsequent dose escalation cohorts, for the intermittent 
dosing schedule evaluated, MLN0128 is administered at approximately 24 hours following paclitaxel infusion during Weeks 1-3.  For example, in the QDx3d QW dosing 
schedule, MLN0128 will be administered on Days 2-4, 9-11, 16-18, and 22-24 of each 4-week cycle; and, in the QDx5d QW dosing schedule, MLN0128 will be administered 
on Days 2-6, 9-13, 16-20, and 22-26 of each 4-week cycle.  Electrolyte levels should be corrected as needed prior to MLN0128 dosing on days when paclitaxel is not 
administered. On days that paclitaxel is administered (with or without trastuzumab), electrolyte levels should be corrected prior to paclitaxel or trastuzumab dosing.
18. Paclitaxel 80 mg/m2 will be given intravenously weekly on Days 1, 8 (±1 day), and 15 (±1 day) of every 28-day cycle according to the FDA label and institution’s standard 
clinical practice.  Concomitant medications used prior to and during the administration of paclitaxel will be recorded on the appropriate CRF pages.  Prior to Amendment 1, 
on days when paclitaxel was administered, MLN0128 was to be given orally in the clinic within 30 minutes of completion of the paclitaxel infusion; and upon implementation 
of Amendment 1, MLN0128 will be given orally at approximately 24 hours following paclitaxel infusion.  If paclitaxel dosing is altered ±1 day, MLN0128 administration 
should also be altered accordingly.  Electrolyte levels should be corrected as needed prior to paclitaxel dosing (see footnote 19 for days when trastuzumab is administered).
19. Once the MTD of MLN0128P (MTDMLN0128P) is determined for the dosing schedules evaluated, Arm B of the expansion phase will enroll HER2+ cancer subjects.  These 
subjects will receive weekly trastuzumab in combination with MLN0128P at the MTDMLN0128P on Days 1, 8 (±1 day), 15 (±1 day) and 22 (±1 day) of every 28-day cycle.  
Trastuzumab 4 mg/kg loading dose will be given on C1D1, with subsequent weekly doses at 2 mg/kg thereafter.  For subjects entering expansion Arm B already receiving 
trastuzumab, the C1D1 dose will be 2 mg/kg if the last trastuzumab dose had been administered within 28 days.  If the last trastuzumab dose was administered >28 days 
before C1D1, then the 4 mg/kg loading dose will be administered.  Trastuzumab will be administered intravenously prior to paclitaxel and according to the FDA label and 
institution’s standard clinical practice. On Day 22 (±1 day) when paclitaxel is not administered, MLN0128 will be administered within 30 minutes of the completion of the 
trastuzumab infusion. Concomitant medications used prior to and during the administration of trastuzumab will be recorded on the appropriate CRF pages.  Electrolyte levels 
should be corrected as needed prior to trastuzumab dosing when trastuzumab is administered before paclitaxel.
20. Termination visit will be done within 30 days of last dose of MLN0128 or paclitaxel or trastuzumab, whichever is discontinued last.
21. Upon implementation of Amendment 2 subjects in the expansion phase were not required to return to clinic on C1D2.
22. The assessment does not need to be repeated if it was done within 3 days prior to the first dose.
23. 12 lead ECG 4 hours (± 30 min) after MLN0128 dosing on Day 1 for subjects enrolled on the original protocol and 4 hours (± 30 min) post-dose on Day 2 for subjects 
enrolled following implementation of Amendment 1. Upon implementation of Amendment 2, ECG is only performed for subjects in the dose escalation phase on C1D2.
24. Tumor assessments will only be done on subjects who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
15
Table 2.2   
Schedule of Events – Cycle 2 and Subsequent Cycles
Assessments
Treatment
Termination 
Visit18
Cycle 2
Cycles 3 and 4
Cycles 5 and Onward
Day 1
Day 
216
Day 8
(±1 
day)
Day 
15
(±1 
day)
Day 
22
(±1 
day)
Day 
1
Day 8
(±1 
day)
Day 
15
(±1 
day)
Day 
22
(±1 
day)
Day 
1
Day 8 
(±1 day)
Day 15 
(±1 day)
Day 22
(±1 day)17
Pre-
dose
Day 
1
Vital Signs, Weight and ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exam1
X1
X
X
X
X1
X
X
X
X1
X
X
X
X1
12-lead ECG2
X
X
Hematology3
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry4
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/INR, PTT)
X
X
X
X
X
X
Fasting Serum Glucose5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Glycosylated Hemoglobin (HbA1c)
X19
X19
X
Fasting Lipid Profile6
X
X
X
X
Urinalysis7
X
X
X
X
X
X
X
X
X
PK Timing8
X
X
X
Radiographic Tumor Evaluation 
and Tumor Markers9
X
X
X20
In-Home Daily Fasting Glucose 
Monitoring10
X
X
X
X
X
X
X
X
X
X
X
X
X
AE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MLN0128 Treatment12
X
X
X
X
X
X
X
X
X
X
X
X
X
Paclitaxel Administration13
X
X
X
X
X
X
X
X
X
Trastuzumab Administration14 –
Only in Arm B of Expansion Phase
X
X
X
X
X
X
X
X
X
X
X
X
ECHO/MUGA15
X15
X15
X15


MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
16
1.
All subjects will undergo complete physical exams on Day 1 of every cycle and at the Termination visit.  All subjects will undergo symptom directed physical exams on Days 
8 (±1 day), 15 (±1 day), and 22 (±1 day) in Cycles 2, 3, and 4.  All subjects will undergo symptom directed physical exams on Days 8 (±1 day) and 15 (±1 day), and, 
additionally for subjects receiving MLN128PH, on Day 22 (±1 day) in Cycles 5 and beyond.
2.
All scheduled ECGs should be performed after the patient has rested quietly for at least 5 minutes in a supine position.  When the timing of ECG assessments coincides with a 
blood collection, the ECG should be obtained before the nominal time of the blood collection.  In some cases, it may be appropriate to repeat an abnormal ECG to rule out 
improper lead placement as contributing to the ECG abnormality.
3.
CBC including WBC with differential, Hgb, Hct, and platelet count.  CBC results performed pre-dose on Days 1, 8, 15, and 22 of every cycle must be available and reviewed 
by the investigator prior to trastuzumab, paclitaxel, or MLN0128 dosing.
4.
Full chemistry panel includes Chem 7 (sodium [Na], potassium [K], chloride [Cl], bicarbonate [CO2], blood urea nitrogen [BUN], creatinine [Cr], glucose), liver function tests 
(LFTs - ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin), LDH, total protein, calcium, phosphate, and magnesium.  Chem 7 and LFT results performed pre-
dose on Days 1, 8, 15, and 22 of every cycle must be available and reviewed by the investigator prior to trastuzumab, paclitaxel, or MLN0128 dosing.  Electrolyte levels 
should be corrected as needed prior to MLN0128 dosing, or prior to paclitaxel or trastuzumab dosing on days when paclitaxel or trastuzumab are administered 24 hours before 
MLN0128 dosing.
5.
Fasting serum glucose will be performed prior to dexamethasone premedication for subjects receiving MLN0128P or prior to trastuzumab infusion for subjects receiving 
MLN0128PH, and included in the Chem 7 panel on Days 1, 8, 15, and 22 of every cycle prior to dosing.  Subjects are required to fast overnight (nothing to eat or drink by 
mouth except water after midnight or a minimum of 8 hours) for all of these measurements.
6.
Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein (LDL-C), triglycerides.
7.
Urinalysis will include macroscopic assessment of the amount of protein, glucose, white blood cells and blood if they are present (levels should be recorded if available) and 
microscopic analysis should be performed if an abnormality is noted.  Microscopic urinalysis will also be performed along with 12-hour urine collection and spot urine 
electrolytes, protein and creatinine and serum chemistry at any time when the serum creatinine is ≥ Grade 1 according to NCI CTCAE version 4.0.
8.
Plasma PK samples will be obtained for subjects in the dose escalation phase prior to determination of the MLN0128P MTD at the following time points prior to Amendment 
1:  pre-dose, immediately at the end of paclitaxel infusion (EOPI and pre-MLN0128 dose), and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 
min), and 6 hours (± 30 min) post-MLN0128 dose on C2D1.  Upon implementation of Amendment 1, plasma PK samples will be obtained for subjects in the dose escalation 
phase of the study at the following time points: on C2D1, pre-dose, immediately at EOPI, and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 min), 
and 6 hours (± 30 min) post-paclitaxel infusion completion; and on C2D2, pre-MLN0128 dose, and at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (± 30 min), 4 hours (± 30 
min), and 6 hours (± 30 min) post-MLN0128 C2D2 dose.
9.
CT (with contrast)/MRI of chest, abdomen and pelvis and relevant tumor markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA) will be obtained every 2 cycles (+ 
7 days) starting at C3D1 for response assessment by RECIST version 1.1.  A confirmatory scan should be performed at approximately 4 weeks from the previous scan for all 
subjects with an objective response of ≥ PR.  The same method (CT with contrast or MRI) must be used throughout the study.
10. Subjects will continue to monitor their daily fasting blood glucose levels at home with a glucometer and will be instructed to notify the study doctor when the fasting glucose 
is abnormal.  The early detection and treatment of hyperglycemia has been key in managing this drug-related adverse event effectively in previous human studies with 
MLN0128.  Each institution should decide an abnormal fasting glucose level (ie, ≥ 140 mg/dL) where the treatment and close monitoring of hyperglycemia might be required.
11. Concomitant medications will be collected from 30 days prior to the first dose of study drug (MLN0128, paclitaxel, or trastuzumab) until termination of the study.
12. Prior to Amendment 1, MLN0128 was to be given orally on an intermittent schedule consisting of daily administration of MLN0128 for 3 days on, 4 days off repeated each 
week (QDx3d QW of a 4-week cycle).  On days when weekly paclitaxel is administered (Days 1, 8 [±1 day], and 15[±1 day] of every 28-day cycle), MLN0128 was to be 
administered in the clinic to the subject within 30 minutes of the completion of paclitaxel infusion.  On Day 22 (±1 day) when paclitaxel is not administered, MLN0128 was 
to be administered alone for subjects receiving MLN0128P and within 30 minutes of the completion of trastuzumab infusion for subjects receiving MLN0128PH.  Upon 
implementation of Amendment 1 in subsequent dose escalation cohorts, for the intermittent dosing schedule evaluated, MLN0128 is administered at approximately 24 hours 
following paclitaxel infusion.  For example, in the QDx3d QW dosing schedule, MLN0128 will be administered on Days 2-4, 9-11, 16-18, and 22-24 of each 4-week cycle; 
and, in the QDx5d QW dosing schedule, MLN0128 will be administered on Days 2-6, 9-13, 16-20, and 22-26 of each 4-week cycle.  Electrolyte levels should be corrected as 


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needed prior to MLN0128 dosing on days when paclitaxel is not administered.  On days that paclitaxel is administered (with or without trastuzumab) electrolyte levels should 
be corrected prior to paclitaxel or trastuzumab dosing.
13. Paclitaxel 80 mg/m2 will be given intravenously weekly on Days 1, 8 (±1 day), and 15 (±1 day) of every 28-day cycle according to the FDA label and institution’s standard 
clinical practice.  Prior to Amendment 1, on days when paclitaxel was administered, MLN0128 was given orally in the clinic within 30 minutes of completion of the paclitaxel 
infusion; and upon implementation of Amendment 1, MLN0128 is given orally at approximately 24 hours following paclitaxel infusion.  If paclitaxel dosing is altered ±1 day, 
MLN0128 administration should also be altered accordingly.  Concomitant medications used prior to and during the administration of paclitaxel will be recorded on the 
appropriate CRF pages.  Electrolyte levels should be corrected as needed prior to paclitaxel dosing (see footnote 14 for days when trastuzumab is administered).
14. Once the MTD of MLN0128P (MTDMLN0128P) is determined for the dosing schedules evaluated, Arm B of the expansion phase will enroll HER2+ cancer subjects.  These 
subjects will receive weekly trastuzumab in combination with MLN0128P at the MTDMLN0128P on Days 1, 8 (±1 day), 15 (±1 day), and 22 (±1 day) of every 28-day cycle.  
Trastuzumab 2 mg/kg will be given weekly starting with C1D8 (±1 day).  Trastuzumab will be administered intravenously prior to paclitaxel and according to the FDA label 
and institution’s standard clinical practice.  On Day 22 (±1 day) when paclitaxel is not administered, MLN0128 will be administered within 30 minutes of the completion of 
trastuzumab infusion.  Concomitant medications used prior to and during the administration of trastuzumab will be recorded on the appropriate CRF pages.  Electrolyte levels 
should be corrected as needed prior to trastuzumab dosing when trastuzumab is administered before paclitaxel.
15. ECHO/MUGA should be performed every 3 cycles in subjects receiving MLN0128PH, starting with C4D1, and at the Termination visit.
16. Upon implementation of Amendment 2, subjects in the expansion phase were not required to return to clinic on C2D2.
17. Day 22 (±1 day) clinic visit will be only required for subjects receiving MLN0128PH.
18. Termination visit will be within 30 days of last dose of MLN0128 or paclitaxel or trastuzumab, whichever is discontinued last.
19. HbA1c should be performed on Day 1 every 3 months starting with C4D1.
20. Tumor assessments will only be done on subjects who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.


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3
TABLE OF CONTENTS
1    TITLE PAGE .....................................................................................................................1
CLINICAL STUDY PROTOCOL.........................................................................................1
RATIONALE FOR AMENDMENT 7...................................................................................2
PURPOSES FOR AMENDMENT 7......................................................................................2
PROTOCOL APPROVAL PAGE .........................................................................................3
2
SYNOPSIS..........................................................................................................................4
2.1
Schedule of Events....................................................................................................12
3
TABLE OF CONTENTS ................................................................................................18
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................23
5
INTRODUCTION............................................................................................................27
5.1
Clinical Experience with MLN0128.........................................................................27
5.1.1
Clinical Safety.............................................................................................27
5.1.2
Clinical Pharmacokinetics...........................................................................28
5.2
Study Rationale.........................................................................................................29
5.3
Summary of Overall Risks and Benefits...................................................................30
6
STUDY OBJECTIVES....................................................................................................33
7
INVESTIGATIONAL PLAN .........................................................................................34
7.1
Overall Study Design and Plan.................................................................................34
7.2
Dose Escalation Phase ..............................................................................................34
7.2.1
Dose Limiting Toxicity ...............................................................................34
7.2.2
Maximum Tolerated Dose...........................................................................35
7.2.3
Dose Escalation Plan to Determine the Maximum Tolerated Dose............35
7.2.4
Expansion Phase..........................................................................................37
7.2.5
Intra-Subject Dose Escalation .....................................................................37
7.2.6
Dose Modification or Treatment Delay for Toxicity ..................................37
7.2.6.1
Dose Modification for Paclitaxel and MLN0128-Related 
Toxicities......................................................................................37
7.2.6.2
Dose Modification for Trastuzumab-Related Toxicities .............46
7.2.7
Management of Hyperglycemia ..................................................................47
7.2.8
Subjects with Possible Cardiac Instability ..................................................47
7.3
Discussion of Study Design, Including Choice of Control Group............................47
7.4
Selection of Study Population...................................................................................48
7.4.1
Inclusion Criteria.........................................................................................48
7.4.2
Exclusion Criteria........................................................................................49
7.4.3
Removal of Subjects from Treatment or Assessment .................................50
7.4.4
Subject Identification and Replacement of Subjects...................................51


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7.5
Treatments.................................................................................................................52
7.5.1
Treatments Administered ............................................................................52
7.5.2
Identity of Investigational Product (IP) MLN0128.....................................52
7.5.2.1
MLN0128 Product Characteristics...............................................52
7.5.3
Storage and Labeling of MLN0128.............................................................52
7.5.4
Directions for Administration of Study Medications..................................53
7.5.4.1
MLN0128.....................................................................................53
7.5.4.2
Paclitaxel Administration.............................................................54
7.5.4.3
Trastuzumab Administration .......................................................54
7.5.5
MLN0128-related Product Complaints.......................................................55
7.5.6
Method of Assigning Subjects to Treatment Groups..................................55
7.5.7
Selection of MLN0128 Doses Used in the Study........................................55
7.5.8
Selection of Timing of Dose of MLN0128 for Each Subject......................56
7.5.9
Blinding.......................................................................................................56
7.5.10 Prior and Concomitant Medications............................................................56
7.5.11 Treatment Compliance ................................................................................57
7.6
Investigational Product Accountability.....................................................................57
7.6.1
Return and Disposition of Clinical Supplies...............................................58
7.7
Dietary or Other Protocol Restrictions......................................................................58
7.8
Efficacy and Safety Variables...................................................................................58
7.8.1
Efficacy and Safety Measurements Assessed .............................................58
7.8.2
Safety Variables ..........................................................................................58
7.8.2.1
Acquisition of 12-Lead Electrocardiograms................................59
7.8.2.2
Review of 12-Lead Electrocardiograms ......................................59
7.8.2.3
Review of Clinically Significant Electrocardiographic 
Abnormalities...............................................................................59
7.8.3
Efficacy Variables .......................................................................................60
7.8.4
Additional Variables....................................................................................60
7.8.4.1
Pharmacokinetics .........................................................................60
7.8.4.2
Pharmacodynamics ......................................................................60
7.8.4.2.1
Biomarkers of TORC1/2 Target Inhibition..................60
7.8.4.2.2
Exploratory Apoptotic Biomarkers..............................60
7.8.4.2.3
Exploratory Predictive Biomarkers of Activity...........60
8
ADVERSE EVENTS .......................................................................................................61
8.1
Definitions.................................................................................................................61
8.1.1
Pretreatment Event Definition.....................................................................61
8.1.2
Adverse Event Definition............................................................................61


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8.1.3
Serious Adverse Event Definition...............................................................61
8.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events .........................................................................................................62
8.3
Monitoring of Adverse Events and Period of Observation.......................................63
8.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.......64
9
APPROPRIATENESS OF MEASUREMENTS...........................................................65
9.1
Pharmacokinetics ......................................................................................................65
9.2
Biomarker Assessments ............................................................................................65
9.2.1
Pharmacodynamic Assessments..................................................................65
9.2.2
Assessments of Predictive Biomarkers of Activity.....................................65
10 STUDY PROCEDURES .................................................................................................66
10.1 Screening and Baseline Assessments........................................................................66
10.2 Treatment Visit(s) .....................................................................................................67
10.2.1 Cycle 1.........................................................................................................67
10.2.1.1
Cycle 1 Week 1............................................................................67
10.2.1.1.1
Cycle 1 Day1................................................................67
10.2.1.1.2
Cycle 1 Day 2...............................................................69
10.2.1.2
Cycle 1 Week 2 (Cycle 1 Day 8±1).............................................69
10.2.1.3
Cycle 1 Week 3 (Cycle 1 Day 15±1)...........................................70
10.2.1.4
Cycle 1 Week 4 (Cycle 1 Day 22±1)...........................................71
10.2.2 Cycle 2.........................................................................................................72
10.2.2.1
Cycle 2 Week 1 (Cycle 2 Day 1) .................................................72
10.2.2.2
Cycle 2 Week 1 (Cycle 2 Day 2) .................................................73
10.2.2.3
Cycle 2 Weeks 2 and 3 (Cycle 2 Days 8±1 and 15±1) ................74
10.2.2.4
Cycle 2 Week 4 (Cycle 2 Day 22±1)...........................................75
10.2.3 Cycle 3 and Cycle 4.....................................................................................76
10.2.3.1
Cycles 3 and 4 Week 1 (Cycles 3 and 4 Day 1±1) ......................76
10.2.3.2
Cycles 3 and 4 Week 2 (Cycles 3 and 4 Day 8±1) ......................77
10.2.3.3
Cycles 3 and 4 Week 3 (Cycles 3 and 4 Day 15±1) ....................78
10.2.3.4
Cycles 3 and 4 Week 4 (Cycles 3 and 4 Day 22±1) ....................79
10.2.4 Cycle 5 and Onward....................................................................................79
10.2.4.1
Cycle 5 and Onward Week 1 (Cycle 5 and onward Day 1±1......79
10.2.4.2
Cycle 5 and Onward Week 2 (Cycle 5 and Onward Day 8±1)....81
10.2.4.3
Cycle 5 and Onward Week 3 (Cycle 5 and Onward Day 15±1)..81
10.2.4.4
Cycle 5 onward Week 4 (Cycle 5 onward Day 22±1).................82
10.3 Termination Visit......................................................................................................83
11 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........85


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11.1 Analysis Endpoints ...................................................................................................85
11.1.1 Primary Endpoints.......................................................................................85
11.1.1.1
Dose Escalation Phase: ................................................................85
11.1.1.2
Expansion Phase: .........................................................................85
11.1.2 Secondary Endpoints...................................................................................85
11.1.3 Safety and Tolerability Endpoints...............................................................86
11.2 Analysis Populations.................................................................................................86
11.2.1 Safety Analysis............................................................................................86
11.2.2 Efficacy Analysis ........................................................................................87
11.3 Statistical Methods....................................................................................................87
11.3.1 Safety Analysis............................................................................................87
11.3.2 Efficacy Analysis ........................................................................................88
11.4 Sample Size Determination.......................................................................................89
11.4.1 Dose Escalation Phase.................................................................................89
11.4.2 Expansion Phase..........................................................................................89
11.5 Interim Analysis and Early Stopping Guidelines......................................................90
11.6 Changes in the Conduct of the Study or Planned Analyses......................................90
12 ETHICS ............................................................................................................................92
12.1 Institutional Review Board or Ethics Committee .....................................................92
12.2 Ethical Conduct of Study..........................................................................................92
12.3 Subject Information and Informed Consent..............................................................92
13 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...................94
14 CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................95
15 STUDY MONITORING AND AUDITING ..................................................................96
16 RETENTION OF RECORDS ........................................................................................97
17 DISCLOSURE OF DATA...............................................................................................98
18 REFERENCES.................................................................................................................99
19 PROTOCOL ACCEPTANCE PAGE..........................................................................100
20 APPENDICES................................................................................................................101
20.1 Appendix A:  ECOG Performance Status Scale.....................................................101
20.2 Appendix B:  A LIST OF STRONG CYP3A4, CYP2C9 AND CYP2C19 
INDUCERS/INHIBITORS.....................................................................................102
20.3 Appendix C  New York Heart Association Classification of Cardiac Disease ......103
20.4 Appendix D:  Amendment 7 Summary of Changes ...............................................104


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Clinical Study Protocol INK128-003 Amendment 7
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LIST OF TABLES
Table 2.1 
Schedule of Events – Cycle 1........................................................................12
Table 2.2   
Schedule of Events – Cycle 2 and Subsequent Cycles..................................15
Table 7.1 
Definition of Dose-Limiting Toxicity ...........................................................35
Table 7.2 
Maximum Tolerated Dose Determination and Cohort Expansion................36
Table 7.3 
Guidelines for Paclitaxel and MLN0128 Dose Modification and Delay ......38
Table 7.4 
Guidelines for MLN0128, Paclitaxel, and Trastuzumab Dose 
Modification and Delay Due to Cardiotoxicity.............................................46
Table 11.1 
Date of Progression or Censoring for Duration of Response........................89


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MLN0128
Clinical Study Protocol INK128-003 Amendment 7
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26
PTT
Partial Thromboplastin Time
QD
once a day
QDx3d QW
once a day 3 on 4 days off repeated each week
QDx5d QW
once a day 5 days on 2 days off repeated each week
QT
interval on ECG between the start of the Q wave and end of the T wave
QTc
QT interval corrected for heart rate
QW
once weekly
Rapalog
rapamycin analog
RECIST
Response Evaluation Criteria in Solid Tumors
S6
ribosomal protein S6
S6K
ribosomal S6 kinase
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
t1/2
plasma half-life
Tmax
time of maximum plasma concentration
TORC
target of Rapamycin Complex
TSC1/2
tuberous sclerosis complex 1/2
ULN
Upper Limit of Normal
US
United States
WBC
white blood cell
Definition of Terms:
Investigational Product (IP) or Study Drug:
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in 
a clinical trial, including a product with a marketing authorization when used or assembled 
(formulated or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an approved use.” (from 
E6 International Conference on Harmonisation [ICH] 1.33)
The terms “IP” and “study drug” may be used interchangeably in the protocol.


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5
INTRODUCTION
MLN0128 (formerly INK128) is a potent and highly selective, Adenosine Tri-Phosphate (ATP)-
competitive inhibitor of the serine/threonine kinase termed as the mammalian target of 
rapamycin (mTOR).  MLN0128 is mechanistically distinct from the allosteric inhibitors of 
mTOR (rapamycin and its derivatives, referred to as rapalogs).  The rapalogs inhibit mTOR 
complex 1 only; this is distinct from MLN0128 that inhibits both mTOR complex 1 (mTORC1) 
and mTOR complex 2 (mTORC2).  MLN0128 is formulated as capsules intended for the 
treatment of solid and hematologic malignancies.
A comprehensive review of MLN0128 is contained in the Investigator’s Brochure (IB) supplied 
by Millennium Pharmaceuticals, Inc. (Millennium).  The investigator should review this 
document before initiating this study.
5.1
Clinical Experience with MLN0128
5.1.1
Clinical Safety
The safety and tolerability of single-agent MLN0128 administration is being studied in this first-
in-human (FIH), phase 1, dose-finding study in subjects with advanced solid malignancies and a 
second phase 1 study (Study INK128-002) in subjects with multiple myeloma and non-Hodgkin 
lymphoma, including Waldenström Macroglobulinemia.  A third phase 1b trial (Study INK128-
003) is evaluating MLN0128 in combination with paclitaxel in subjects with advanced solid 
malignancies.
Repeated in 28-day cycles, the dosing regimens (and dose ranges) studied to date in INK128-001 
are the following:  once daily (QD; 2-7 mg), once weekly (QW; 10-40 mg), once daily for 
3 consecutive days per week (QD3d QW; 6-20 mg), and once daily for 5 consecutive days per 
week (QD5d QW; 7-13 mg).  As of 09 December 2012, dose-limiting toxicities have included 
hyperglycemia, asthenia, fatigue, mucositis, and rash.  SAEs attributed to MLN0128 have 
included hyperglycemia, asthenia, mucosal inflammation, stomatitis, esophagitis, nausea, 
anemia, renal failure, cardiac arrest, and ventricular fibrillation.
There have been 5 deaths during the study attributable to (1 subject each) pleural effusion, small 
intestinal obstruction, cancer pain, disease progression, and cardiac arrest.  The only death 
considered related to study drug was due to cardiac arrest in a subject receiving 6 mg QD.
Regardless of causality, adverse events (AEs) with intensity Grade 3 have been reported in 
10% of subjects and include hyperglycemia, asthenia, mucosal inflammation, anemia, 
lymphopenia, hypophosphatemia, and rash.  Inclusive of all grades, the most frequently reported 
AEs (those with 20% incidence) include hyperglycemia, asthenia, fatigue, mucosal 
inflammation, decreased appetite, nausea, vomiting, diarrhea, rash, and pruritus.


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As of 09 December 2012, there have been 2 dosing regimens studied in INK128-002.  In 
repeated 28-day cycles, they are QD (2-7 mg) and QD3d QW (9-12 mg).  DLTs have included 
asthenia, fatigue, mucosal inflammation, rash, urticaria, and thrombocytopenia.  None of 
the13 SAEs reported was attributed to MLN0128.  Two subjects have died during the study of 
events not related to MLN0128:  1 death was due to subdural bleeding, and the other death was 
due to an unspecified cause.  Regardless of causality, AEs with intensity Grade 3 reported in at 
least 2 subjects include fatigue, mucosal inflammation, neutropenia, thrombocytopenia, 
hypocalcemia, hypophosphatemia, and pneumonia.  Inclusive of all grades, the most frequently 
reported AEs (those with 20% incidence) include hyperglycemia, fatigue, stomatitis, decreased 
appetite, nausea, vomiting, diarrhea, anemia, and thrombocytopenia.
As of 09 December 2012, the MLN0128 dosing regimens (and dose ranges) studied in 
INK128-003 are QD3d QW (6-10 mg), QD5d QW (7 mg), and QW (30 and 40 mg).  
MLN0128 is administered in combination with paclitaxel (80 mg/m2) administered on Days 1, 8, 
and 15 of each 28-day cycle.  The dose escalation phase of this study has completed and the 
administration of MLN0128 plus paclitaxel with or without trastuzumab is being evaluated in the 
expansion phase.  Observed DLTs include fatigue, mucosal inflammation, rash, nausea, diarrhea, 
leukopenia, neutropenia, and thrombocytopenia.  SAEs observed with the MLN0128 + paclitaxel 
are dehydration, diarrhea, vomiting, and mucositis.  There have been 7 deaths during the study 
including 4 due to disease progression, and 1 death each due to myocardial infarction, enlarging 
tumor mass causing tracheal compression, and pneumonia.  None of these deaths were attributed 
to MLN0128 or paclitaxel.  Regardless of causality, AEs with intensity Grade 3 reported in at 
least 2 subjects are hyperglycemia, fatigue, diarrhea, dehydration, neutropenia, and 
hypophosphatemia.  Inclusive of all grades, the most frequently reported AEs (those with 20% 
incidence) include hyperglycemia, asthenia, fatigue, mucosal inflammation, anorexia, rash, 
nausea, vomiting, diarrhea, dehydration, hypokalemia, hypophosphatemia, anemia, neutropenia, 
urinary tract infection, and constipation.
Details on these studies are provided in the MLN0128 IB.
5.1.2
Clinical Pharmacokinetics
MLN0128 displays high oral bioavailability and predicable PK with minimal levels of steady 
state accumulation.  It is rapidly absorbed with Tmax occurring between 1 to 4 hours following 
oral administration.  The mean elimination half-life of MLN0128 ranged from approximately 
7 to 11 hours across 4 dose levels.  The mean accumulation index of MLN0128 following 
multiple doses ranged from 0.7-fold to 1.7-fold.  The mean steady-state plasma concentrations 
(Cmax,ss) ranged from 52 to 232 nM.  Comparisons of plasma exposures (Cmax and area under the 
plasma concentration-time curve from 0 to 24 hr [AUC0-24]) following oral doses of MLN0128 
suggest dose-linear plasma pharmacokinetics.


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5.2
Study Rationale
The mTOR is a kinase that regulates cell growth, translational control, angiogenesis and cell 
survival by integrating nutrient and hormonal signals.  mTOR plays a key role in several 
pathways that are frequently dysregulated in human cancer.(1)  The mTOR activity in the 
intracellular signaling complexes (mTORC1 and mTORC2) is an important therapeutic target 
because (i) it is a key intracellular point of convergence for a number of cellular signaling 
pathways; (ii) it appears to be a stable target that does not mutate; (iii) inhibiting mTOR may 
inhibit abnormal cell proliferation, tumor angiogenesis and abnormal cellular metabolism. Thus, 
mTOR inhibitors may be effective as single agents and may enhance the efficacy of other cancer 
treatments.
mTOR operates in 2 distinct multi-protein complexes, mTORC1 and mTORC2.  mTORC1, 
stimulated by growth factors and amino acids, regulates cell growth by controlling the activity of 
the ribosomal protein S6 (S6) kinases and eukaryotic initiation factor 4E-binding Protein (4EBP) 
proteins.(2)  Rapamycin (Rapamune®) is an mTORC1 inhibitor that has been approved for 
prophylaxis of organ rejection in subjects receiving renal transplants.  Although rapamycin has 
been shown to possess some antitumor activity, its poor aqueous solubility and chemical stability 
has precluded its utilization at doses necessary for anticancer treatment.  This led to development 
of new analogues of rapamycin (rapalogs).  Those currently in clinical development as anticancer 
agents include temsirolimus (cell cycle inhibitor-779 or CCI-779), everolimus (RAD-001), and 
deforolimus (AP23573).  These agents have demonstrated antiproliferative activity against a 
range of malignancies in preclinical studies and clinical evaluations have revealed some 
encouraging data in selected disease populations.  In 2007, temsirolimus was approved by the US 
Food and Drug Administration (FDA) for treatment of advanced renal cell cancer and in March 
2009, everolimus was approved for treatment of advanced renal cancer after failure of treatment 
with sunitinib or sorafenib.(3, 4) Despite some encouraging clinical data, the rapalogs have 
limitations and efficacy may be confined to distinct subject subtypes or diseases.  There are 
several scientific hypotheses that may explain the limited success of rapalogs.  Inhibition of 
mTORC1 (without inhibition of mTORC2) leads to activation of AKT kinase due to a feedback 
mechanism, and this upregulation of AKT may actually accelerate tumor progression, thus 
limiting the clinical efficacy of rapalogs.(5)
Additionally, mTORC2 phosphorylates AKT which is required for full activity of AKT.  
Activated AKT is involved in cancer cell survival, proliferation, growth, metabolism, 
angiogenesis and metastasis. Inhibition of AKT activity through mTORC2 inhibition has been 
explored for anticancer therapeutics and preclinical investigations have shown inhibition of 
mTORC2 blocks cancer growth.(6) mTORC2 inhibition can also reverse the feedback activation 
of AKT induced by mTORC1 inhibition. Therefore, mTOR inhibitors that target both mTOR 
complexes such as MLN0128 may achieve greater clinical efficacy than rapalogs.(7)


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Combination of MLN0128 with paclitaxel inhibited tumor cell proliferation more effectively 
than either of the single agent in preclinical experimental models.  In most instances, 
MLN0128/paclitaxel combination led to an increase in cell cycle arrest and apoptosis. In vivo, 
MLN0128/paclitaxel combination in xenograft models of endometrial and breast cancers 
displayed enhanced anti-tumor efficacy and blockade of TORC1/2 signaling in a dose dependent 
manner.  Tumor re-growth upon stop of drug treatment was further delayed by the combination 
as compared to treatment with either of the single agents.  The combination of MLN0128 and 
paclitaxel was well tolerated in mouse xenograft tumor models (unpublished data from 
Intellikine labs).
To date, this study (INK128-003) has evaluated MLN0128 administration in combination with 
paclitaxel on a QDx3d QW dosing schedule in subjects with advanced solid malignancies.  
Amendment 1 will evaluate additional dosing schedules for MLN0128 administration in 
combination with paclitaxel (such as QDx5d QW dosing) to maximize tolerability and exposure 
of the doublet combination and further defines the expansion cohort patient population beyond 
HER2+ breast cancer.  Recent preclinical in vivo xenograft data also suggest that administration 
of MLN0128 approximately 24 hours, instead of within 30 minutes, following paclitaxel infusion 
may provide more synergy in tumor cell kill; therefore, for subsequent cohorts opened following 
Amendment 1, MLN0128 will be administered approximately 24 hours following paclitaxel 
administration.
5.3
Summary of Overall Risks and Benefits
Currently, 206 subjects have participated in phase 1 studies including 145 subjects in 
single-agent studies INK128-001 and INK128-002 (N = 106 and N = 39, respectively); and 
61 subjects in the paclitaxel combination study INK128-003.  Toxicities have been mostly 
Grades 1 and 2, reversible, and manageable with supportive care and/or interruption or dose 
reduction of study drug.  Commonly reported study drug-related AEs have included 
hyperglycemia, asthenia, fatigue, mucosal inflammation, decreased appetite, rash, nausea, 
vomiting, and diarrhea.  This emerging safety profile is consistent with those of other TORC1/2 
and PI3K pathway inhibitors.
As of 2012, there are no FDA-approved TORC1/2 inhibitors.  Rapamycin and rapalogs are 
TORC1 inhibitors with well-described toxicity profiles.  Common toxicities include the 
following:  immunosuppression with the potential to increase the risk of both nonserious and 
serious infections, and/or malignancies; mucositis, stomatitis, and mouth sores with a frequency 
from 41% to 78%; anorexia (approximately 30%), pneumonitis including interstitial lung disease 
(5%-36%); diarrhea (25%-56%); skin toxicity (48%-66%) which manifests typically as 
maculopapular or acneform rash, skin dryness, eczema, skin discoloration, and nail dystrophy; 
hyperlipidemia (hypercholesteremia and/or hypertriglyceridemia) with incidences from 8% to 


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44%; hyperglycemia (8%-22%); thrombocytopenia (10%-33%); anemia (27%-94%); leucopenia 
(27%-38%); hypokalemia (11%-21%); hypophosphatemia (15%-49%); hypertension (4%-7% in 
renal cancer subjects); elevated serum creatinine (37%-57%); elevated liver function tests 
(approximately 20%); arthralgia (25%-30%); asthenia (about 30%); and peripheral edema (24%-
35%).(3, 4, 8, 9)  Serious infections have included sepsis, opportunistic infections, and even death.  
An increase in the development of lymphomas is also a possibility because of the 
immunosuppression.  Additionally, hypersensitivity reactions (18%), and fatal bowel perforation 
(1%) have been reported.  Rapidly progressive, and sometimes fatal, acute renal failure not 
clearly related to renal cancer disease progression, abnormal wound healing, and increased risk 
of developing intracerebral bleeding (including fatal outcomes) in subjects with central nervous 
system (CNS) malignancies and/or receiving anticoagulation therapy have been reported in 
subjects receiving temsirolimus.  Because of potential hazard to the developing fetus, women of 
childbearing potential are advised to avoid becoming pregnant while receiving rapamycin or 
rapalogs.(3, 4, 9)
The toxicities of rapamycin or rapalogs are typically reversible and infrequently serious.  
MLN0128 targets both TORC1 and TORC2, and thus may prove to have a different risk/benefit 
profile from the rapalogs.  There is no human information available on inhibition of TORC2 
alone.  The safety profile of MLN0128 continues to be explored in advanced malignancies, 
including non-Hodgkin lymphoma (NHL), and hematologic malignancies.
Paclitaxel is an antimicrotubule agent approved by the FDA and EMA for treatment of breast, 
ovarian, and non-small cell lung cancers.  Common side effects (≥ 10%) observed with paclitaxel 
include: neutropenia or leucopenia, thrombocytopenia, anemia, infections, bleeding, red cell 
transfusions, peripheral neuropathy, hypersensitivity reaction, myalgia/arthralgia, hypotension, 
abnormal electrocardiograms (ECGs), nausea and vomiting, mucositis, alopecia, ALT (SGOP) 
elevation, elevated alkaline phosphatase, and injection site reaction.
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% of patients 
receiving paclitaxel in clinical trials. Fatal reactions have occurred despite premedication. All 
subjects should be pretreated according to the package insert Taxol® package insert.(10)
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that binds to the 
extracellular domain of the human epidermal growth factor receptor 2 protein (HER2) and is 
approved by the FDA and EMA for the treatment of breast and gastric cancer with HER2 
overexpression. The most common serious adverse reactions (≥ 5%) associated with 
trastuzumab infusion (Herceptin®) include pain, asthenia, fever, chills, headache, abdominal 
pain, back pain, infection, flu symptom, accident injury, allergic reaction, tachycardia, 
congestive heart failure (7% as a single agent and 28% in combination with anthracycline and 


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cyclophosphamide), nausea, diarrhea, vomiting, peripheral edema and edema, bone pain, 
arthralgia, insomnia, dizziness, parenthesis, depression, increased cough, dyspnea, rhinitis, 
pharyngitis, sinusitis, and rash.(11)
Based on the limited safety data from Study INK128-001 thus far, it does not appear that 
MLN0128 has overlapping toxicities of neutropenia, peripheral neuropathy or cardiomyopathy 
which frequently limit paclitaxel and/or trastuzumab administration.


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7
INVESTIGATIONAL PLAN
7.1
Overall Study Design and Plan
This is a phase 1, open-label study consisting of a dose-escalation phase in advanced solid 
malignancies to determine the MTD of oral administration of MLN0128 (QDx3dQW on a 
4-week cycle) or via alternate dosing schedules (such as 5 days on, 2 days off repeated weekly 
[QDx5d QW]) in combination with an infusion of paclitaxel on Days 1, 8, and 15 of each cycle 
(MLN0128P), followed by an expansion phase at the MLN0128P MTD (MTDMLN0128P) ± 
trastuzumab in up to 25 additional subjects for further safety and preliminary efficacy.  A cycle 
will be defined as 4 weeks.
Once the MTDMLN0128P is determined for each of the dosing schedules evaluated, an additional 
6 subjects may be enrolled at the MTDMLN0128P for further safety and PK evaluation.  A dose and 
schedule will be selected for the expansion phase which may enroll subjects into 2 arms in 
parallel:

Arm A will consist of HER2- cancer subjects receiving MLN0128P at the MTDMLN0128P

Arm B will consist of HER2+ cancer subjects receiving MLN0128P at the MTDMLN0128P
plus weekly trastuzumab (MLN0128PH)
7.2
Dose Escalation Phase
The dose-escalation phase of the study is to determine the MTD and the DLT of MLN0128 when 
given orally on Days 1-3 each week of a 4-week cycle (QDx3d QW) or via alternate dosing 
schedules (such as QDx5d QW) in combination with paclitaxel on Days 1, 8, and 15 of each 
cycle (MLN0128P) in subjects with advanced solid malignancies.  A cycle is defined as 4 weeks.
7.2.1
Dose Limiting Toxicity
Adverse events will be graded according to the NCI-CTCAE v4.0.  A copy of this grading scale 
will be provided to the study sites upon request or can be accessed at 
http://ctep.cancer.gov/forms/CTCAEv4.pdf.
Dose-limiting toxicity is defined as either of the following occurring during Cycle 1 
(Days 1 - 28) and attributable to MLN0128P as shown in Table 7.1.


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Table 7.1   
Definition of Dose-Limiting Toxicity

Grade ≥ 3 non-hematologic toxicity, except for
o
Alopecia;
o
Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all subjects should receive 
optimal antiemetic and/or antidiarrheal prophylaxis and/or treatment);
o
Grade 3 hyperglycemia lasting ≤ 14 days (all subjects should receive optimal antihyperglycemic treatment)
o
Grade 3 rash lasting ≤ 3 days (all subjects should receive topical steroid treatment, oral antihistamines, and 
pulse oral steroids, if necessary)

Grade 3 thrombocytopenia with hemorrhage

Grade 4 neutropenia lasting > 7 days in the absence of growth factor support

Grade 4 neutropenia of any duration associated with fever 38.5°C and/or infection 

Any other Grade 4 hematologic toxicity 

Inability to administer at least 75% of doses of MLN0128 within Cycle 1 due to drug-related toxicity

Any clinically significant occurrence which the Investigators and Sponsor agree would place subjects at undue 
safety risk
Subjects who experience an AE that meets the definition for a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted.  If the event resolves to Grade 1 or 
baseline values within 28 days of interrupting planned therapy, and in the opinion of the 
investigator and the Sponsor’s Medical Monitor, the benefits of continuing treatment outweigh 
the risks posed by the toxicity, subjects may continue study treatment with paclitaxel (at the 
same dose or at a 25% dose reduction) and MLN0128 (at a dose based on the AE and guidance 
provided in Table 7.3) with approval of the Sponsor’s Medical Monitor.  Subjects receiving 
MLN0128 at a starting dose of 6 mg will have MLN0128 dose- reduced to ≥ 4 mg if dose 
reduction is required.
The Sponsor’s Medical Monitor should be contacted prior to any dose modification in paclitaxel 
or MLN0128 for any subject in the study.
7.2.2
Maximum Tolerated Dose
The MTD of MLN0128P (MTDMLN0128P) is defined as the highest dose level of MLN0128 when 
given orally for each dosing schedule evaluated (ie, QDx3d QW or QDx5d QW each week) of a 
4-week cycle in combination with paclitaxel (80 mg/m2) on Days 1, 8, and 15 of each cycle at 
which no more than 1 out of 6 subjects experiences a DLT during the first cycle (28 days) of
therapy.
7.2.3
Dose Escalation Plan to Determine the Maximum Tolerated Dose
Cohorts of 3 to 6 subjects with advanced solid malignancies will be enrolled at each MLN0128
dose level evaluated in combination with paclitaxel in 4-week cycles.  Subjects at each dose level 
will be treated and observed for DLT through the end of the first cycle.  Each subject will 
participate in only 1 cohort and 1 dosing schedule.


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The starting dose of MLN0128 is 6 mg daily for the first 3 days (Days 1-3) of each week.  Dose 
escalation will only proceed if no DLT is observed in a cohort of 3 subjects.  If a DLT is 
observed in only 1 subject in a cohort of 3 subjects, an additional 3 subjects may be enrolled up 
to a total of 6 subjects at this dose level.  Dose escalation will then only proceed if no more than 
1 subject in the cohort of 6 subjects has experienced a DLT during the first cycle of treatment.  If 
a DLT is observed in 2 or more subjects in a cohort of 3 or 6 subjects, an additional 3 subjects 
will be enrolled for a total of 6 subjects at the previous lower dose level, if only 3 subjects were 
treated at that lower dose level.  If a DLT is observed in 2 or more subjects in a cohort of 3 to 6 
subjects treated with the starting dose of 6 mg, a new cohort of 3-to 6 subjects will be enrolled at 
either 4 mg or an intermediate dose level between 4 mg and 6 mg. Table 7.2 below provides a 
summary of the dose escalation decision rules for determination of the MTD.
Table 7.2   
Maximum Tolerated Dose Determination and Cohort Expansion
Number of Subjects per Cohort With a 
DLT During the Cycle 1 (Days 1 to 21)
Dose Escalation Decision Rule
0 out of 3
Enter 3 subjects at the next dose level.
1 out of 3
Enter up to 3 more subjects at this dose level.
If none of the 3 additional subjects has a DLT, proceed to the next 
dose level.
If 1 or more of the 3 additional subjects has a DLT, then dose 
escalation will be stopped, and the MTD will have been exceeded.  
Up to 3 additional subjects may be entered at a lower dose level if 
only 3 subjects were treated previously at that dose or a new cohort 
of 3 subjects at an intermediate dose level may be evaluated.
2
Dose escalation will be stopped, and the MTD will have been 
exceeded.  Up to 3 additional subjects will be entered at a lower dose 
level if only 3 subjects were treated previously at that dose or a new 
cohort of 3 subjects at an intermediate dose level may be evaluated.
1 out of 6 at the highest dose evaluated.
This is generally the MTD.  
Abbreviations:  DLT = dose limiting toxicity; MTD = maximum tolerated dose.
All participating sites are required to send in DLT notification forms within 24 hours of learning 
of the event (details will be provided in Study Reference Manual).  Dose-limiting toxicities will 
immediately be communicated to all participating sites via emails and/or conference calls.  
Additionally, site teleconferences between the Sponsor and all participating sites will be held 
approximately every 1 to 2 weeks during the dose escalation phase to discuss any suspected 
AEs/DLTs that have occurred in subjects within each cohort.  Participating Investigators and the 
Sponsor’s Medical Monitor will review study drug-related toxicities from the current cohort 
during the site teleconferences before escalating to the next dose level or starting a lower dose.


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7.2.4
   Expansion Phase
After the MTDMLN0128P has been identified, 2 arms of subjects will be enrolled in parallel. 
Approximately 30 subjects may be enrolled in the expansion phase of the study: 

Arm A will consist of approximately 12 to 15 safety-evaluable HER2- cancer subjects 
receiving MLN0128P at the MTDMLN0128P.  Additional subjects may be enrolled into 
lower dose cohorts of MLN0128P of Arm A.

Arm B will consist of approximately 12 to 15 safety-evaluable HER2+ cancer subjects 
receiving MLN0128P at the MTDMLN0128P plus weekly trastuzumab (MLN0128PH).  Up 
to 3 subjects will be enrolled initially in Arm B and observed for one cycle prior to 
enrolling additional subjects into this arm.  Additional subjects may be enrolled into 
lower dose cohorts of MLN0128P + trastuzumab of Arm B.
It is estimated that in total up to 75 subjects may be enrolled in the study.
7.2.5
Intra-Subject Dose Escalation
Once the MTDMLN0128P is determined, intra-subject dose escalation is only allowed (at the 
Investigator’s discretion and with the Sponsor’s approval) in subjects actively receiving 
MLN0128P at a dose lower than the MTDMLN0128P for a minimum of 8 weeks in the absence of 
disease progression or unacceptable treatment-related toxicity.
7.2.6
Dose Modification or Treatment Delay for Toxicity
7.2.6.1
Dose Modification for Paclitaxel and MLN0128-Related Toxicities
The Investigator should try to the best of his/her ability to assess whether an adverse event is 
possibly related to study drug, and if so, attribute it to MLN0128 only, paclitaxel only, or 
MLN0128 and paclitaxel, and treat the subject accordingly.  This section and Table 7.3 below 
provides suggested guidelines for the management of various study drug-related toxicities in 
subjects receiving paclitaxel and MLN0128.
Paclitaxel dosing should be withheld for ≥ Grade 2 paclitaxel-related toxicities and resumed at 
the same dose or at a 25% dose reduction, which refers to a decrease of 20 mg/m2 depending on 
the timing of recovery and number of episodes occurred (see Table 7.3 and Table 7.4).  If 
paclitaxel dosing is delayed due to paclitaxel-related toxicities for > 2 consecutive planned 
treatment weeks despite supportive treatment per standard clinical practice or more than 2 dose 
reductions of paclitaxel (≤40 mg/m2) is required, stop paclitaxel therapy.
In general, MLN0128 dosing should be withheld for ≥ Grade 2 renal insufficiency or ≥Grade 3 
MLN0128-related non-hematologic toxicities.


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Table 7.3 below provides suggested guidelines for the investigator to use along with his/her best 
judgment for MLN0128 and paclitaxel dose delay and/or reduction based on the AE observed.  
Subjects with a starting dose of 6 mg MLN0128 will have the dose reduced to ≥ 4 mg if dose 
reduction is required.  If MLN0128 dosing is delayed due to MLN0128-related toxicities for > 28 
consecutive days despite supportive treatment per standard clinical practice or more than 2 dose 
reductions of MLN0128 is required, stop MLN0128 and paclitaxel therapy, discontinue the 
subject from the study, and complete the follow-up visit within 30 days of the last administration 
of MLN0128 or paclitaxel, whichever is discontinued last.
The Sponsor’s Medical Monitor should be contacted prior to any dose modification in paclitaxel 
and/or MLN0128 for any subject in the study.
Table 7.3   
Guidelines for Paclitaxel and MLN0128 Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction 
and/or Delay
Paclitaxel Dose Reduction and/or Delay
Absolute Neutrophil Count (ANC) 
Grade 2 < 1500 - 1000/mm3
No change.  Continue MLN0128 at same 
dose and schedule.
No change.  Continue paclitaxel at 
same dose and schedule.
For ANC ≤ 1500/mm3 consider the use 
of prophylactic myeloid growth factors 
(ie, GCSF)

Start one or two days after 
paclitaxel infusion and use for 2–6 
days according to subject’s need, at 
physician discretion, and to avoid 
dose reduction.

Growth factor should not be given 
on the same day as paclitaxel 
infusion.

GCSF is preferred over peg-
filgrastim due to the weekly dosing 
of paclitaxel in this study.
Grade 3 < 1000 500/mm3
No change.  Continue MLN0128 at same 
dose and schedule.
Consider use of prophylactic myeloid 
growth factor support per guidelines 
above.
Hold paclitaxel until ANC > 1000/mm3
Resume paclitaxel based on timing of 
recovery and number of previous 
episodes:

≤ 2 weeks of interrupting planned 
therapy
o
First episode—no change to 
paclitaxel dose
o
≥Second episode—reduce 
paclitaxel dose by 25% for all 
subsequent cycles

> 2 weeks of interrupting planned 
therapy—stop paclitaxel and 
discontinue subject from study


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Consider use of prophylactic myeloid 
growth factor support per guidelines 
above.
Grade 4 < 500/mm3
Hold MLN0128 until ANC > 1000/mm3
Resume MLN0128 based on timing of 
recovery:

≤ 1 week—no change to MLN0128
dose

> 1 but ≤ 2 weeks—reduce 
MLN0128 to the next lower dose 
level or an intermediate dose level 
that is between the current and next 
lower dose for all subsequent 
cycles 

> 2 weeks—stop MLN0128 and 
discontinue subject from study
Consider use of prophylactic myeloid 
growth factor support per guidelines 
above.
Hold paclitaxel until ANC > 1000/mm3
Resume paclitaxel based on timing of 
recovery and number of previous 
episodes: 

≤ 2 weeks of interrupting planned 
therapy
o
First episode—no change to 
paclitaxel dose
o
≥ Second episode—reduce 
paclitaxel dose by 25% for all 
subsequent cycles

> 2 weeks of interrupting planned 
therapy—stop paclitaxel  and 
discontinue subject from study
Consider use of prophylactic myeloid 
growth factor support per guidelines 
above.
Neutropenic Fever 
ANC ≤ 1000/mm3,
fever ≥ 38.5°C 
Hold MLN0128 until ANC > 1000/mm3
and fever < 38.5°C.
Resume MLN0128 according to the 
number of episodes that are resolved to 
Grade ≤1 or baseline values within 2 
weeks:

First episode: resume MLN0128 at 
same dose and schedule.

Second episode: resume MLN0128
at same dose and schedule.

Third episode: reduce MLN0128
dose to the next lower dose level or 
an intermediate dose level that is 
between the current and next lower 
dose for all subsequent cycles.

Fourth episode: reduce MLN0128
dose to the next lower dose level 
from the reduced or an intermediate 
dose level for all subsequent cycles.

Fifth episode: stop MLN0128 and 
discontinue subject from study.
Consider use of prophylactic myeloid 
growth factor support per guidelines 
above.
Hold paclitaxel until ANC > 1000/mm3
and fever < 38.5°C.
Resume paclitaxel according to the 
number of episodes that are resolved to 
Grade ≤1 or baseline values within 2 
weeks:

First episode: resume paclitaxel at 
same dose and schedule.

Second episode: reduce paclitaxel 
dose by 25% from starting dose (60 
mg/m2) for all subsequent cycles.

Third episode: reduce paclitaxel 
dose by 25% from starting dose 
(60mg/m2) for all subsequent 
cycles.

Fourth episode: reduce paclitaxel 
dose by 50% from starting dose (40 
mg/m2) for all subsequent cycles.

Fifth episode: stop paclitaxel and 
discontinue subject from study.
Consider use of prophylactic myeloid 
growth factor support per guidelines 
above.


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Thrombocytopenia 
Grade 1 (≥ 75,000/mm3) 
No change.  Continue MLN0128 at same 
dose and schedule.
No change.  Continue paclitaxel at 
same dose and schedule.
Grade 2 (50-74,999/mm3)
No change.  Continue MLN0128 at same 
dose and schedule
Hold paclitaxel until platelets 
> 75,000/mm3
Resume paclitaxel based on timing of 
recovery within 2 weeks of interrupting 
planned therapy:

≤1 week—no change to paclitaxel

> 1 but ≤ 2 weeks of interrupting

> 2 weeks of interrupting planned 
therapy—stop paclitaxel and 
discontinue subject from study
Grade 3 (25–44,999/mm3 )
Hold MLN0128 until platelets 
> 75,000/mm3
Resume MLN0128 based on timing of 
recovery within 2 weeks:

≤ 1 week—no change to MLN0128
dose

> 1 but ≤ 2 weeks—reduce 
MLN0128 dose to the next lower 
dose level or an intermediate dose 
level that is between the current and 
next lower dose for all subsequent 
cycles 

> 2 weeks—stop MLN0128 and 
discontinue subject from study
Platelet transfusions in the absence of 
bleeding should not be administered.
Hold paclitaxel until platelets 
> 75,000/mm3
Resume paclitaxel based on timing of 
recovery within 2 weeks of interrupting 
planned therapy:

≤1 week—no change to paclitaxel

> 1 but ≤ 2 weeks of interrupting 
planned therapy—reduce paclitaxel 
dose by 25% for all subsequent 
cycles 

> 2 weeks of interrupting planned 
therapy—stop paclitaxel and 
discontinue subject from study
Platelet transfusions in the absence of 
bleeding should not be administered.
Grade 4 (< 25,000/mm3) 
Hold MLN0128 until platelets 
≥75,000/mm3
Resume MLN0128 according to the 
number of episodes that are resolved to 
Grade ≤1 or baseline values within 2 
weeks:

First episode: resume MLN0128 at 
same dose and schedule.

Second episode: reduce MLN0128
dose to the next lower dose level or 
an intermediate dose level that is 
between the current and next lower 
dose for all subsequent cycles.

Third episode: reduce MLN0128
dose to the next lower dose level 
from the first reduced dose or an 
intermediate dose level for all 
subsequent cycles.

Fourth episode: stop MLN0128 and 
Hold paclitaxel until platelets 
≥75,000/mm3
Resume paclitaxel according to the 
number of episodes that are resolved to 
Grade ≤ 1 or baseline values within 2 
weeks:

First episode: reduce paclitaxel by 
25% from starting dose (60mg/m2) 
for all subsequent cycles.

Second episode: reduce paclitaxel 
dose by 25% from starting dose (60 
mg/m2) for all subsequent cycles.

Third episode: reduce paclitaxel 
dose by 50% from starting dose (40 
mg/m2) for all subsequent cycles.

Fourth episode: stop paclitaxel and 
discontinue subject from study.
Platelet transfusions should be 


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discontinue subject from study. 
Platelet transfusions should be 
administered prophylactically if platelets 
≤10,000/mm3 or as clinically indicated 
if there is bleeding.
administered prophylactically if 
platelets ≤10,000/mm3 or as clinically 
indicated if there is bleeding.
Anemia 
≥ 2 g/dL decrease in Hgb 
from baseline 
No change.  Continue MLN0128 at 
same dosing and schedule, support 
with RBC transfusions as clinically 
indicated, and rule out bleeding.
Continue or reduce MLN0128 dose 
according to the number of 
episodes that are resolved to ≤ 
Grade 1 or baseline values within 2 
weeks:

First and second episodes: 
continue MLN0128 at same 
dose and schedule.

Third episode: reduce 
MLN0128 dose to the next 
lower dose level or an 
intermediate dose level that is 
between the current and next 
lower dose for all subsequent 
cycles.

Fourth episode: Continue 
MLN0128 dose. at the 
previously reduced dose while 
paclitaxel dose is reduced 
again

Fifth episode: stop MLN0128
and discontinue subject from 
study.
Consider erythropoietin growth 
factor support.
Hold paclitaxel, support with RBC 
transfusions as clinically indicated, and rule 
out bleeding.
Resume paclitaxel according to the number 
of episodes that are resolved to Grade ≤ 1 or 
baseline values within 2 weeks:

First episode: resume paclitaxel at same 
dose and schedule.

Second episode: reduce paclitaxel dose 
by 25% from starting dose (60 mg/m2) 
for all subsequent cycles.

Third episode: continue paclitaxel at 
60 mg/m2 for all subsequent cycles when 
MLN0128 dose is reduced

Fourth episode: reduce paclitaxel dose by 
50% from starting dose (40 mg/m2) for 
all subsequent cycles.

Fifth episode: stop paclitaxel and 
discontinue subject from study.
Consider erythropoietin growth factor 
support.
Hepatic 
Grade 1 
No change.  Continue MLN0128 at 
the same dose and schedule.
No change.  Continue paclitaxel at the same 
dose and schedule.


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Grade 2 
Hold MLN0128 until LFTs 
improve to ≤Grade 1 or baseline 
values within 2 weeks.
Resume MLN0128 based on timing 
of recovery:

≤ 1 week—no change to 
MLN0128 dose

> 1 but ≤ 2 weeks—reduce 
MLN0128 dose to the next 
lower dose level or an 
intermediate dose level that is 
between the current and next 
lower dose for all subsequent 
cycles

> 2 weeks—stop MLN0128
and discontinue subject from 
study
A rise in indirect bilirubin with a 
normal direct bilirubin believed to 
be attributable to Gilbert‘s disease 
does not require a change or hold 
in MLN0128 dosing.  Gilbert’s 
disease should be documented in 
the subject’s medical history CRF 
page.
Hold paclitaxel until LFTs improve to 
≤Grade 1 or baseline values within 2 weeks 
of interrupting planned therapy.
Resume paclitaxel based on time of 
recovery:

≤ 1 week—no change to paclitaxel dose

> 1 but ≤ 2 weeks of interrupting planned 
therapy—reduce paclitaxel dose by 25% 
for all subsequent cycles

> 2 weeks of interrupting planned 
therapy—stop paclitaxel and discontinue 
subject from study
A rise in indirect bilirubin with a normal 
direct bilirubin believed to be attributable to 
Gilbert‘s disease does not require a change 
or hold in MLN0128 dosing.  Gilbert’s 
disease should be documented in the 
subject’s medical history CRF page.
Grade ≥3 
Hold MLN0128 until LFTs 
improve to ≤Grade 1 or baseline 
values within 2 weeks.
Resume MLN0128 according to 
the number of episodes that are 
resolved to ≤ Grade 1 or baseline 
values:

First episode: resume 
MLN0128 at the same dose 
and schedule.

Second episode: reduce 
MLN0128 dose to the next 
lower dose level or an 
intermediate dose level that is 
between the current and next 
lower dose for all subsequent 
cycles.

Third episode: reduce 
MLN0128 dose to the next 
lower dose level from the 
reduced dose or an 
intermediate dose level for all 
subsequent cycles.

Fourth episode: stop MLN0128
and discontinue subject from 
Hold paclitaxel until LFTs improve to 
≤Grade 1 or baseline values within 2 weeks 
of interrupting planned therapy.
Resume paclitaxel according to the number 
of episodes that are resolved to ≤ Grade 1 or 
baseline:

First episode: reduce paclitaxel dose by 
25% (60 mg/m2) from starting dose for 
all subsequent cycles.

Second episode: reduce paclitaxel dose 
by 25% (60 mg/m2) from starting dose 
for all subsequent cycles.

Third episode: reduce paclitaxel dose by 
50% (45 mg/m2) from starting dose for 
all subsequent cycles.

Fourth episode: stop paclitaxel and 
discontinue subject from study.


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study.
Renal (Creatinine)
Grade 1 (> ULN-1.5x ULN 
or > 1-1.5 x baseline)
No change.  Continue MLN0128 at 
same dose and schedule.  Rule out 
prerenal azotemia and consider IV 
hydration.
Collect the following tests to help 
identify cause of renal dysfunction:

Chemistry 7

Urinalysis

12-hour urine collection 

Spot urine for electrolytes, 
protein, creatinine
No change.  Continue paclitaxel at same 
dose and schedule.  Rule out prerenal 
azotemia and consider IV hydration.
Collect the following tests to help identify 
cause of renal dysfunction:

Chemistry 7

Urinalysis

12-hour urine collection

Spot urine for electrolytes, protein, 
creatinine
Grade 2 (>1.5-3x ULN or 
>1.5-3.0 x baseline)
Hold MLN0128 until creatinine 
improves to ≤ Grade 1 or baseline 
values in ≤ 2 weeks.
Collect the following tests to help 
identify cause of renal dysfunction:

Chemistry 7

Urinalysis

12-hour urine collection 

Spot urine for electrolytes, 
protein, creatinine
Consider IV hydration.
Resume MLN0128 based on timing 
of recovery:

≤ 1 week—no change to 
MLN0128 dose

> 1 but ≤ 2 weeks—reduce 
MLN0128 to the next lower 
dose level or an intermediate 
dose level that is between the 
current and next lower dose
for all subsequent cycles 

> 2 weeks—stop MLN0128
and discontinue subject from 
study
Hold paclitaxel until creatinine improves to 
≤ Grade 1 or baseline values in ≤ 2 weeks of 
interrupting planned therapy.
Collect the following tests to help identify 
cause of renal dysfunction:

Chemistry 7

Urinalysis

12-hour urine collection 

Spot urine for electrolytes, protein, 
creatinine
Consider IV hydration.
Resume paclitaxel at the same dose and 
schedule.
Grade ≥ 3 (>3-6x ULN/>3 
baseline or >6 ULN)
Hold MLN0128 until creatinine 
improves to ≤ Grade 1 or baseline 
values in ≤ 2 weeks.
Collect the following tests to help 
identify cause of renal dysfunction:

Chemistry 7
Hold paclitaxel until creatinine improves to 
≤ Grade 1 or baseline values ≤ 2 weeks of 
interrupting planned therapy.
Collect the following tests to help identify 
cause of renal dysfunction:

Chemistry 7


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
Urinalysis

12-hour urine collection

Spot urine for electrolytes, 
protein, creatinine
Consider IV hydration.
Resume MLN0128 based on timing 
of recovery:

≤ 1 week—no change to 
MLN0128 dose

> 1 but ≤ 2 weeks—reduce 
MLN0128 to the next lower 
dose level or an intermediate 
dose level that is between the 
current and next lower dose  
for all subsequent cycles 

> 2 weeks—stop MLN0128
and discontinue subject from 
study

Urinalysis

12-hour urine collection

Spot urine for electrolytes, protein, 
creatinine
Consider IV hydration.
Resume paclitaxel based on timing of 
recovery:

≤ 1 week—no change to paclitaxel dose

> 1 but ≤ 2 weeks of interrupting planned 
therapy—reduce paclitaxel dose by 25% 
for all subsequent cycles 

> 2 weeks of interrupting planned 
therapy—stop paclitaxel and discontinue 
subject from study
Peripheral Neuropathy
Grade ≤ 2
No change.  Continue MLN0128 at 
same dose and schedule.
No change.  Continue paclitaxel at same 
dose and schedule.
Grade ≥ 3
Continue MLN0128 during the first 
week when paclitaxel treatment is 
interrupted.

If peripheral neuropathy does 
not improve to Grade ≤ 2 after 
one week of paclitaxel 
treatment interruption, hold 
MLN0128 for one week

Resume MLN0128 at the 
next lower dose level or an 
intermediate dose level that 
is between the current and 
next lower dose if the event 
recovers to Grade ≤ 2 after 
one week of MLN0128
interruption (two weeks of 
paclitaxel interruption)

Stop MLN0128 if the event 
does not recover to Grade ≤ 2 
after one week of MLN0128
Hold planned paclitaxel for one week to see 
if peripheral neuropathy improves to Grade 
≤ 2.

Reduce paclitaxel dose by 25% for all 
subsequent cycles if peripheral 
neuropathy improves to Grade ≤ 2 after 
one week of paclitaxel planned 
treatment interruption

If peripheral neuropathy does not 
improve to Grade ≤ 2 after one week of  
planned paclitaxel treatment 
interruption, continue to hold paclitaxel 
treatment while MLN0128 treatment is 
held
o
Resume paclitaxel by 25%  dose 
reduction for all subsequent cycles 
if the event recovers to Grade ≤ 2 
after two weeks of paclitaxel 
interruption (one week of 
MLN0128 interruption)

Stop paclitaxel if the event does not 
recover to Grade ≤ 2 after two weeks of  
planned paclitaxel treatment 
interruption (one week of MLN0128
interruption)


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interruption (two weeks of 
paclitaxel interruption) 
Hyperglycemia
Grade ≤ 2
ULN – 250 mg/dL
Continue MLN0128 at same dose 
and schedule.  Refer to Section 
7.2.7 for guidelines on 
hyperglycemia management.
Continue paclitaxel at same dose and 
schedule.  Refer to Section 7.2.7 for 
guidelines on hyperglycemia management.
Grade ≥ 3
>250 mg/dL
Hold MLN0128 until 
hyperglycemia improves to Grade 
≤ 2.  Refer to Section 7.2.7 for 
guidelines on hyperglycemia 
management.
Optimize hyperglycemia therapy 
and resume MLN0128 based on 
timing of recovery:  

≤ 1 weeks – resume MLN0128
at same dose and schedule

> 1 but ≤ 2 weeks – reduce 
MLN0128 dose to the next 
lower dose level or an 
intermediate dose level that is 
between the current and next 
lower dose for all subsequent 
cycles

> 2 weeks – stop MLN0128
and discontinue subject from 
study
Continue paclitaxel at same dose and 
schedule.  Refer to Section 7.2.7 for 
guidelines on hyperglycemia management.
Rash
Grade ≤ 2
Continue MLN0128 at same dose 
and schedule.  Consider treatment 
with topical steroid cream/ointment 
and/or oral antihistamines.
Continue paclitaxel at same dose and 
schedule.  Consider treatment with topical 
steroid cream/ointment and/or oral 
antihistamines.
Grade ≥3
Hold MLN0128 until rash 
improves to Grade ≤ 2.  Consider 
treatment with topical steroid 
cream/ointment, oral 
antihistamines, and/or oral pulse 
steroids.
Resume MLN0128 based on timing 
of recovery:  

≤ 2 weeks – reduce MLN0128
dose to the next lower dose 
level or an intermediate dose 
level that is between the 
current and next lower dose
for all subsequent cycles

> 2 weeks – stop MLN0128
Continue paclitaxel at same dose and 
schedule.  Consider treatment with topical 
steroid cream/ointment, oral antihistamines, 
and/or oral pulse steroids.


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and paclitaxel and discontinue 
subject from study
7.2.6.2
Dose Modification for Trastuzumab-Related Toxicities
During the expansion phase of the study, subjects in Arm B will receive trastuzumab in 
combination with MLN0128P at the MTDMLN0128P.  There is no dose reduction schedule for 
trastuzumab administration in this study.  If an AE is assessed by the Investigator as mainly 
related to trastuzumab, such as congestive heart failure, trastuzumab administration should be 
held and appropriate measures taken per standard clinical practice and per the FDA label.  If the 
subject’s cardiac dysfunction does not recover back to baseline after 4 weeks of withholding 
trastuzumab and trastuzumab will be permanently discontinued, MLN0128 and paclitaxel should 
also be discontinued and the subject taken off the study.  Table 7.4 below provides guidelines on 
the management of trastuzumab-related cardiotoxicity in subjects receiving MLN0128PH.  If an 
adverse event may be related to the combination of MLN0128PH, the guidelines provided in 
Table 7.3 above may be followed for dose modification and/or delay of MLN0128 and/or 
paclitaxel.
Table 7.4   
Guidelines for MLN0128, Paclitaxel, and Trastuzumab Dose Modification 
and Delay Due to Cardiotoxicity
Adverse Event
MLN0128
Paclitaxel
Trastuzumab
Asymptomatic 
decline in 

LVEF > 15% 
from baseline 
values OR

LVEF 10-15% 
from baseline 
values and is 
below 
institution’s LLN
No change.  Continue 
MLN0128 at same dose 
and schedule.
No change.  Continue 
paclitaxel at same dose and 
schedule.
Hold trastuzumab for 4 
weeks.
Reassess LVEF at 4 weeks:

If LVEF has recovered 
to baseline or absolute 
decline from baseline is 
< 15%, resume 
trastuzumab at same 
dose and schedule.

If LVEF has not 
recovered back to 
baseline or absolute 
decline from baseline is 
> 15%, stop 
trastuzumab, 
MLN0128, and 
paclitaxel and 
discontinue the subject 
from the study.
Symptomatic cardiac 
dysfunction/congesti
ve heart failure
Stop MLN0128, paclitaxel, and trastuzumab and discontinue the subject from the study.


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7.2.7
Management of Hyperglycemia
In addition to obtaining fasting serum glucose (FSG) levels at the clinic visits as outlined in the 
Schedule of Events, all subjects will be given a glucometer to monitor their daily pre-dose 
fasting blood glucose (FBG) levels at home.  Subjects will be instructed to notify the study staff 
immediately with any abnormal readings for further instructions on the management of their 
hyperglycemia.
In the event that any FSG reading performed at the site indicates hyperglycemia (> upper limit of 
normal [ULN]), the study staff should first ascertain that the subject was fasting at the time of the 
blood draw (ie, nothing by mouth for at least 8 hours prior to blood being obtained) and repeat 
the FSG as needed.  If the repeat FSG continues to demonstrate hyperglycemia, Investigators 
should initiate steps to aggressively manage the hyperglycemia per standard clinical practice.  
The following guidelines are provided to aid the Investigator in initiating antiglycemic therapies.
All subjects developing hyperglycemia on the study should have their glucose closely monitored 
by study staff.  The Investigator may choose to continue monitoring subjects with Grade 1 
hyperglycemia (FSG > ULN ≤ 160 mg/dL) or consider initiating treatment with an oral 
hypoglycemic agent, such as metformin.  All subjects with Grade ≥ 2 hyperglycemia (FSG 
> 160 mg/dL) should be treated aggressively with oral hypoglycemic agents and/or insulin as 
clinically indicated.  The Investigator should consult an endocrinologist if needed to aid in 
optimizing the subject’s hyperglycemia treatment plan.  Refer to Table 7.3 above for guidelines 
on dose modification and/or delay of MLN0128 and paclitaxel.
It is recommended that subjects be initially treated with a fast acting, insulin sensitizer such as 
metformin at 500 mg orally (PO) QD and titrate up to a maximum of 1000 mg PO twice a 
day(BID) as needed.  Concurrent addition to metformin of dipeptidyl peptidase-4 (DPP-4) 
inhibitors (eg, sitagliptin or vildagliptin) and/or insulin should also be considered.  Oral 
sulfonylureas (eg, glipizide or glyburide) should be used with caution due to the higher risk of 
inducing hypoglycemia in subjects. The dose of oral hypoglycemic agents should be adjusted in 
subjects with renal insufficiency.
In the ongoing phase 1 trial of MLN0128 as a single agent in subjects with advanced 
malignancies (Study INK128-001), most episodes of hyperglycemia observed have been Grades 
1 and 2 that have responded quickly to oral metformin.  Since instituting a standard regimen for 
the early treatment of hyperglycemia, no further episodes of Grade 3 hyperglycemia have been 
observed.
7.2.8
Subjects with Possible Cardiac Instability
For subjects showing signs of cardiac instability after MLN0128 dosing, additional monitoring 
on-site before clinic discharge should be considered.
7.3
Discussion of Study Design, Including Choice of Control Group
The proposed study design is standard for Phase I human oncology trials assessing safety and 
tolerability.  Neither a placebo nor an active control will be included in this study.


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7.4
Selection of Study Population
7.4.1
Inclusion Criteria
Individuals eligible to participate in either the dose escalation phase or the expansion phase of 
the study must meet all of the following inclusion criteria:
1
Age ≥ 18 years, including males and females;
2
Subjects must have locally advanced or metastatic solid tumors with the exception of 
primary brain tumor, and have failed or are not eligible for standard of care therapy. 
Subjects with a history of brain metastasis are eligible for the study as long as they meet 
all the following criteria: their brain metastases have been treated, they have no evidence 
of progression or hemorrhage after treatment, have been off dexamethasone for 4 weeks 
prior to first study drug administration, and have no ongoing requirement for 
dexamethasone or anti-epileptic drugs;
3
For Arm A of the expansion phase only, subjects with advanced bladder cancer or 
endometrial cancer will be enrolled and must have received at least 1, but no more than 
2 prior lines of systemic therapy, including adjuvant or hormonal therapy;
4
For Arm B of the expansion phase only, HER2+ cancer is defined as a pathologic 
diagnosis of cancer which is 3+ by immunohistochemistry (IHC) for HER2 or positive 
for HER2 gene amplification by fluorescence in situ hybridization (FISH) and subjects 
must have received at least 1, but no more than 4 prior lines of systemic cytotoxic 
chemotherapy, excluding adjuvant, hormonal, or targeted therapy;
5
Subjects must have received no more than 4 prior lines of systemic cytotoxic 
chemotherapy for advanced or metastatic disease;
6
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1;
7
Subjects must have adequate organ function, including the following:
a.
Bone marrow reserve consistent with: absolute neutrophil count (ANC) 
≥1.5 x109/L; platelet count ≥ 100 x 109/L;  hemoglobin ≥ 9 g/dL without 
transfusion in the last 2 weeks;
b. Hepatic: total bilirubin ≤ 1.5 x upper ULN, transaminases (aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and 
alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) 
≤2.5 x ULN (< 5 x ULN if liver metastases are present);
c.
Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min 
(Cockroft - Gault formula);
d. Metabolic: fasting serum glucose ≤ 130 mg/dL and fasting triglycerides 
≤300 mg/dL; 
8
Left ventricular ejection fraction (LVEF) ≥ 5 absolute percentage points below 
institutional standard of normal as measured by echocardiogram (ECHO) or multiple 
gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration 
(ie, if the institutional normal is 50%, subject’s LVEF may be as low as 45% to be 
eligible for the study);
9
For women of child-bearing potential, negative serum pregnancy test within 14 days 


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prior to the first study drug administration and use of physician-approved method of 
birth control from 30 days prior to the first study drug administration to 90 days 
following the last study drug administration;
10 Male subjects must be surgically sterile or must agree to use physician-approved 
contraception during the study and for 90 days following the last study drug 
administration;
11 Ability to swallow oral medications;
12 Ability to understand and willingness to sign informed consent form prior to initiation of 
any study procedures;
7.4.2
Exclusion Criteria
Individuals who meet any of the following exclusion criteria will not be eligible to participate 
in either the dose escalation phase or the expansion phase of the study:
1
Diagnosis of primary brain tumor;
2
Have received prior cancer or other investigational therapy within 2 weeks prior to the 
first administration of study drug.  For prior therapies with a half life longer than 3 days, 
the interval must be at least 28 days prior to the first administration of study drug and the 
subject must have documented disease progression.  For prior trastuzumab therapy in 
subjects who enroll in Arm B of the expansion phase, the interval since the previous
trastuzumab dose must be at least 7 days;
3
Have initiated hematopoietic growth factors within 1 week prior to the first 
administration of study drug; subjects already receiving hematopoietic growth factors on 
a chronic basis for ≥ 4 weeks are eligible;
4
Chronic systemic corticosteroid (except inhalers) use within 1 week prior to the first 
administration of study drug.  Premedication with dexamethasone prior to paclitaxel 
administration in this study is allowed;
5
Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or 
for an unknown reason that may alter the absorption of MLN0128;
6
Poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with transient 
glucose intolerance due to corticosteroid administration are allowed in this study if all 
other inclusion/exclusion criteria are met;
7
Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system (CNS) disease, active infection, or any other condition 
that could compromise the subject’s participation in the study;
8
Known human immunodeficiency virus (HIV) infection;
9
Pregnancy (positive serum or urine pregnancy test) or breast feeding;
10 Any history of unstable angina, myocardial infarction, New York Heart Association 
(NYHA) Class III or IV heart failure (See Appendix C), and/or pulmonary hypertension;
11 Significant active cardiovascular disease including:
o
Uncontrolled high blood pressure (ie, systolic blood pressure >180 mm Hg, diastolic 
blood pressure > 95 mm Hg)


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o
Grade 3 or higher valvular disease 
o
Grade 3 or higher atrial fibrillation
o
Grade 3 or higher bradycardia 
o
Endocarditis
o
Pulmonary embolism
o
Recent cerebrovascular accident within 6 months prior to enrollment
12 A requirement for inotropic support or serious uncontrolled cardiac arrhythmia (including 
atrial flutter/fibrillation) within 1 year prior to screening 
13 A pacemaker or implantable cardiac defibrillator;
14 Baseline prolongation of the rate-corrected QT interval (QTc) (eg, repeated 
demonstration of QTc interval > 480 milliseconds) (See Section 7.8.2.2);
15 History of congenital long QT syndrome, ventricular fibrillation, ventricular tachycardia 
or torsades de pointes.
Other Considerations for Exclusion
Patients taking strong CYP3A4, and CYP2C19 inhibitors and/or inducers should be considered 
with caution.  Alternative treatments that are less likely to affect MLN0128 metabolism, if 
available, should be considered.  If a patient requires treatment with one or more of the strong 
CYP3A4, and CYP2C19 inhibitors and/or inducers, the medical monitor should be consulted.  
Examples of the strong CYP3A4 and CYP2C19 inhibitors and inducers include (see Appendix 
B):
Strong inhibitors:
CYP3A4: Ketoconazole, itraconozole, ritonavir, mibefradil indinavir, clarithromycin 
CYP2C19: Fluconazole, fluvoxamine, omeprazole, ticlopidine
Strong inducers:
CYP3A4: Rifampin (also a moderate CYP2C19 inducer), phenytoin, carbamazepine, St. John’s 
wort
Patients should not consume food or beverages containing the fruit or juice from grapefruits, 
pomegranates, star fruit, papayas, or Seville oranges within 7 days before first dose of study 
drug.
7.4.3
Removal of Subjects from Treatment or Assessment
Subjects may withdraw their consent to participate in this study at any time without prejudice. 
The Investigator must withdraw from the study any subject who requests to be withdrawn.  A 
subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator and in accordance with his/her clinical judgment.  When possible, the tests and 
evaluations listed for the Termination visit should be carried out.
Millennium must be notified of all subject withdrawals as soon as possible.  Millennium also 
reserves the right to discontinue the study at any time for either clinical or administrative reasons 
and to discontinue participation by an individual Investigator or site for poor enrollment or 
noncompliance.


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Reasons for which the Investigator or Millennium may withdraw a subject from the study 
include, but are not limited to, the following:

Subject experiences disease progression

Subject experiences unacceptable toxicity, ie
o
Subject develops an AE which meets the DLT definition but the AE does not resolve 
to Grade ≤ 1 within 28 days despite optimal treatment per standard clinical practice
o
Subject requires more than 2 dose reductions

Subject experiences toxicity that is determined by the Investigator to be no longer safe for 
the subject to continue therapy

Subject requests to withdraw from the study treatment

Subject requires or has taken medication prohibited by the protocol

Subject is unwilling or unable to comply with the study requirements

Subject was erroneously admitted into the study or does not meet entry criteria

Subject is lost to follow-up

Subject becomes pregnant
Subjects will return for a Termination visit within 30 days after the last administration of 
MLN0128 or paclitaxel or trastuzumab, whichever is discontinued last.  If a subject fails to 
return for scheduled visits, a documented effort must be made to determine the reason. If the 
subject cannot be reached by telephone after 2 attempts, a certified letter should be sent to the 
subject (or the subject’s legally authorized representative, if appropriate) requesting contact with 
the Investigator.  This information should be recorded in the study records.
Prior to enrollment into the study, the Investigator or designee must explain to each subject that 
the subject’s protected health information obtained during the study may be shared with the 
study sponsor, regulatory agencies, and IRB in order to analyze and evaluate study results.  It is 
the Investigator’s (or designee’s) responsibility to obtain written permission to use protected 
health information per country-specific regulations, such as HIPAA in the US, from each subject, 
or if appropriate, the subject’s legally authorized representative.  If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to obtain a written request, 
to ensure that no further data will be collected from the subject and the subject will be removed 
from the study.
7.4.4
Subject Identification and Replacement of Subjects
Each subject will be assigned a unique subject identifier by the Sponsor or designee.  This 
unique identifier will be on all CRF pages.  During dose escalation, subjects who discontinue 
treatment before completing ≥ 75% of planned MLN0128 doses in Cycle 1 for reasons other than 
study drug-related toxicity will be replaced.


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7.5
Treatments
7.5.1
Treatments Administered
All subjects will receive paclitaxel (80 mg/m2) on Days 1, 8, and 15 in combination with 
MLN0128 given either QDx3d QW or QDx5d QW of each 4-week cycle.  Once the 
MTDMLN0128P is reached in the dose escalation phase, Her2+ cancer subjects enrolled into Arm B 
of the expansion phase will also receive trastuzumab weekly in addition to MLN0128P at the 
MTDMLN0128P.
In the absence of unacceptable MLN0128P or MLN0128PH treatment-related toxicity or disease 
progression, subjects may receive MLN0128P or MLN0128PH treatment for up to 1 year at the 
discretion of the Investigator and beyond 1 year with the agreement of the Investigator and the 
Sponsor.  Subjects will remain on study as long as they continue to receive MLN0128, 
paclitaxel, or trastuzumab without additional anticancer therapies.  Millennium and its designee 
will provide the study site with a supply of MLN0128 sufficient for the completion of the study.
7.5.2
Identity of Investigational Product (IP) MLN0128
MLN0128 is a small molecule being developed as a potent, selective inhibitor of mTORC1/2 for 
the treatment of subjects with advanced solid tumors and hematologic malignancies.
7.5.2.1
MLN0128 Product Characteristics
MLN0128 may be supplied in tamper-resistant bottles as capsules containing 1 of 4 dose 
strengths.

MLN0128 capsules, 1 mg

MLN0128 capsules, 3 mg

MLN0128 capsules, 5 mg
Each 1 mg, 3 mg, and 5 mg capsule for oral administration contains 1 mg, 3 mg, and 5 mg 
MLN0128 respectively and the following inactive ingredients: microcrystalline cellulose (solid 
filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule.
7.5.3
Storage and Labeling of MLN0128
At a minimum, each bottle label shipped to the sites will provide the following information: 
batch number/lot number, study identification, required storage conditions, directions for use, 
and region specific caution statements (including “New Drug – Limited by United States federal 
law to investigational use” language).
MLN0128 accountability records will be maintained by the pharmacy or designated drug 
preparation area at the study site.  Upon receipt of MLN0128 supplies, the pharmacist or a 
designated study staff will inventory the MLN0128 supplies and complete the designated section 
of the shipping form. The shipping/inventory form must be sent to Millennium or its designee, as 
instructed.


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MLN0128 should be stored at controlled room temperature 15 to 30 C (59 to 86 F).  All study 
supplies must be kept in a restricted access area.
A complete dispensing log must be maintained for all MLN0128 dispensed and all capsules of 
MLN0128 must be accounted for.
7.5.4
Directions for Administration of Study Medications
7.5.4.1
MLN0128
Prior to Amendment 1, MLN0128 was to be initially administered orally on a QDx3d QW 
schedule.  On days when weekly paclitaxel was administered (Days 1, 8 [±1 day], and 15 [±1 
day] of every 28-day cycle), MLN0128 was to be administered in the clinic within 30 minutes of 
the completion of paclitaxel infusion. With implementation of Amendment 1, alternate dosing 
schedules (such as QDx5d QW) of MLN0128 administration in combination with paclitaxel may 
be evaluated to optimize tolerability and exposure of the combination.  For the intermittent 
dosing schedules (such as QDx3d QW or QDx5d QW), in subsequent dose escalation cohorts, 
MLN0128 will be administered at approximately 24 hours following completion of paclitaxel
infusion.  For example, on the QDx3d QW dose schedule, paclitaxel will be administered on 
Days 1, 8 (±1 day), and 15 (±1 day) and MLN0128 will be administered on Days 2-4, 9-11, 16-
18, and 22-24 of every 4-week cycle.  Likewise, on the QDx5d QW dose schedule, paclitaxel 
will be administered on Days 1, 8 (±1 day), and 15 (±1 day) and MLN0128 will be administered 
on Days 2-6, 9-13, 16-20, and 22-26 of every 4-week cycle.
If paclitaxel administration is altered by ±1 day, MLN0128 administration should also be altered 
accordingly.
On Day 22 (±1 day) when paclitaxel is not administered, MLN0128 will be administered alone 
for subjects receiving MLN0128P and within 30 minutes of the completion of trastuzumab for 
subjects receiving MLN0128PH.  Cycles are repeated every 28 days.
On each clinic day, the site will administer MLN0128 to the subject (the subject should be 
counseled not to take their MLN0128 dose at home on the day of the clinic visit).  Subjects will 
take their prescribed dose orally once in the morning with a meal at approximately the same time 
of day except on Cycle 1 Day 1 (prior to Amendment 1) or Cycle 1, Day 2 (upon implementation 
of Amendment 1), which requires a fasting glucose level post-MLN0128 dose.  At this visit, 
subjects should be dosed with MLN0128, have the fasting glucose drawn, and then be allowed to 
eat a meal.  In cases where a subject misses dosing at his/her dosing time, the subject may still 
take the dose within 12 hours of the regular dosing time with a meal (subjects should not take 2 
consecutive daily doses within 12 hours of each other).  Subjects who vomit shortly after 
receiving MLN0128 will not receive a replacement dose.  If confirmed that the study drug has 
been vomited, the dose should be noted as having been missed.
MLN0128 capsules should not be opened or crushed.  Direct contact with the powder in 
MLN0128 capsules with skin or mucous membranes should be avoided.  If such contact occurs, 
the subject should wash thoroughly with water.


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MLN0128 capsules should be swallowed with water without chewing or sucking the capsule.  If 
the subject chews or sucks the capsules by error, the subject should drink a large glass of water 
(~8 oz).
Prophylactic use of anti-emetic, anti-nausea, and anti-diarrheal medications is encouraged and 
may be used prior to each MLN0128 dosing as needed throughout the study.  Additional details 
will be provided in the Pharmacy Manual.
7.5.4.2
Paclitaxel Administration
Paclitaxel will be administered weekly according to institutional standard of care.
Paclitaxel will be administered on Days 1, 8 (±1 day), and 15 (±1 day) of each cycle at a dose of 
80 mg/m2 as a 1-hour infusion or according to the institutional standard of care for weekly 
paclitaxel administration.  If a subject’s body weight increases or decreases by ≥ 10% from 
baseline during the course of the study, the body surface area and drug dose should be 
recalculated.
All subjects should be premedicated before treatment with paclitaxel according to institutional 
standards (eg, dexamethasone 20 mg orally, administered approximately 12 and 6 hours before 
beginning the paclitaxel infusion or dexamethasone 20 mg IV 30 minutes before the beginning 
the paclitaxel infusion; diphenhydramine 12.5 mg- 50 mg IV 30 to 60 minutes before the 
infusion; and cimetidine 300 mg IV/PO or ranitidine 50 mg IV or 150 mg PO, or famotidine 
20mg IV/PO 30 to 60 minutes before the infusion).  If dexamethasone is used, subjects should be 
closely monitored for hyperglycemia and treated as needed per standard clinical practice and 
according to the guidelines in Section 7.2.7.  On days of paclitaxel infusion, MLN0128 will be 
given orally in the clinic within 30 minutes (prior to Amendment 1) of the completion of 
paclitaxel infusion.  Upon implementation of Amendment 1, MLN0128 will be given orally in 
the clinic or at home approximately 24 hours following paclitaxel infusion.  On Day 22 (±1 day) 
when paclitaxel is not administered, MLN0128 will be administered alone for subjects receiving 
MLN0128P and within 30 minutes of the completion of trastuzumab for subjects receiving 
MLN0128PH.
7.5.4.3
Trastuzumab Administration
Trastuzumab will be administered weekly to subjects with Her2+ cancer enrolled in the 
expansion Arm B.
A loading dose of trastuzumab 4 mg/kg will be given IV over 90 minutes on C1D1, followed by 
2 mg/kg IV over 30 minutes weekly thereafter. For subjects entering expansion Arm B who are 
already receiving trastuzumab, the Cycle 1, Day 1 dose will be 2 mg/kg IV if the previous 
trastuzumab dose had been administered within the last 28 days.  If the last trastuzumab dose 
was administered more than 28 days before Cycle 1, Day 1, then the 4-mg/kg loading dose will 
be administered.  Trastuzumab will be administered intravenously on Days 1, 8 (±1 day), 15 (±1 
day) and 22 (±1 day) of every 28-day cycle prior to paclitaxel administration according to FDA 
approved label and institution’s standard clinical practice. On Day 22 (±1 day) when paclitaxel 
is not administered, MLN0128 will be administered within 30 minutes of the completion of 


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trastuzumab for subjects receiving MLN0128PH.  All treatment doses should be based on actual 
body weight and not ideal body weight. If a subject’s body weight increases or decreases by 
≥10% from C1D1 during the course of the treatment phase, the drug dose should be 
recalculated.
7.5.5
MLN0128-related 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 Millennium or 
designee and report the event.  Whenever possible, the associated product should be maintained 
in accordance with the label instructions pending further guidance from a Sponsor’s Quality 
representative.
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and submitted as described in Section 8.2.
7.5.6
Method of Assigning Subjects to Treatment Groups
The enrollment and treatment assignment will be centrally managed by Millennium and its 
designee.  When a treatment cohort is open for enrollment, sites will fax in a Subject Registration 
Form along with subject eligibility supporting documents for each potential subject to 
Millennium and its designee.  Millennium and its designee will assign a subject number and 
treatment cohort for each subject that is accepted into the study.  Sites cannot enroll or start 
dosing the subject without receiving the assigned subject number and treatment cohort from 
Millennium or its designee.  In the event that more than 1 dosing arm is open for enrollment 
during the dose escalation phase, then a randomization schema provided by the biostatistician 
will be used to assign subjects to a dosing schedule.  Subjects may not participate in more than 1 
dosing arm.
7.5.7
Selection of MLN0128 Doses Used in the Study
The starting dose of MLN0128 for this study is 6 mg daily for the first three days of each week.  
If a DLT is observed in 2 or more subjects in a cohort of 3 to 6 subjects treated with the starting 
dose of 6 mg, a new cohort of 3to 6 subjects will be enrolled at either 4 mg or an intermediate 
dose level between 4 mg and 6 mg.
Dose escalation will be according to a modified Fibonacci schema.  For example, a starting dose 
of 6 mg may be escalated in successive cohorts to 8 mg, 10 mg, etc. or an intermediate dose 
between 2 planned doses may be evaluated.  The level of dose escalation or a decision to go to an 
intermediate dose or a lower dose will be determined after discussion between the participating 
Investigators and Millennium’s Medical Monitor prior to dose escalation, but will not exceed the 
planned next escalated dose according to the modified Fibonacci schema.


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7.5.8
Selection of Timing of Dose of MLN0128 for Each Subject 
The 2 ongoing phase 1 single agent MLN0128 studies in solid tumors and multiple myeloma are 
evaluating the safety, pharmacokinetics, and preliminary efficacy of daily dosing of MLN0128.  
Based on the limited clinical data available, dosing of MLN0128 QDx3d QW should provide 
similar PK parameters, with perhaps a better tolerability profile. The dosing schedules herein are 
based on an understanding of the proposed mechanism of action of MLN0128 as an 
mTORC1/mTORC2 inhibitor and a desire to avoid interference with paclitaxel. MLN0128 has 
been shown to induce G1 cell cycle arrest. Paclitaxel is known to block the progression of cells 
through G2 into mitosis and this G2-M arrest has been proposed to be a prerequisite step for 
apoptosis induced by paclitaxel (Shu et al, 1997).  Pretreatment of mTOR inhibitors will arrest 
cells in G1 phase and antagonize the toxic effect of paclitaxel (Mondesire et al, 2004).  
Therefore, MLN0128 should be given after paclitaxel administration in order not to interfere 
with the mechanism of paclitaxel.  Amendment 1 will evaluate additional dosing schedules for 
MLN0128 administration in combination with paclitaxel (such as QDx5d QW dosing) to 
maximize tolerability and exposure of the doublet combination.  Recent preclinical in vivo 
xenograft data also suggest that administration of MLN0128 approximately 24 hours, instead of 
within 30 minutes, following paclitaxel infusion may provide more synergy in tumor cell kill; 
therefore, for subsequent cohorts opened following Amendment 1, MLN0128 will be 
administered approximately 24 hours following paclitaxel administration. Once Amendment 1 is 
implemented at a given site, all active patients at that site will convert to this new timing at the 
start of the next cycle.
7.5.9
Blinding
This is an open label study with no placebo or comparators.
7.5.10
Prior and Concomitant Medications 
All prescription and over-the-counter medications taken by a subject within 30 days before the 
first study drug administration will be recorded on the designated CRF.
The following medications/therapies are prohibited during the study:

Other investigational agents or mTOR inhibitors

Other anticancer therapies including radiation or surgery  (palliative radiation for pain 
control of pre-existing lesions is allowed with Sponsor approval)

Systemic corticosteroids (either IV or oral steroids, excluding inhalers or premedication 
with dexamethasone prior to paclitaxel administration) during the dose escalation phase 
of the study, unless necessary for treatment of MLN0128-related AE, ie, rash

Anti-epileptic drugs for subjects with treated brain metastasis

Strong CYP3A4 /CYP2C19 inducers/inhibitors (see Appendix B)
If a patient requires treatment with one or more of the strong CYP3A4, and CYP2C19 inhibitors 
and/or inducers, the medical monitor should be consulted.  Examples of the strong CYP3A4 and 
CYP2C19 inhibitors and inducers can be found in Appendix B.


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There are no known strong specific CYP2C9 inhibitors or inducers.  Examples of moderate 
inhibitors of CYP2C9 are fluconazole and miconazole; and moderate inducers of CYP2C9 are 
carbamazepine and rifampin (Appendix B).  These agents show some degree of overlap with 
their modulation of CYP3A4 and CYP2C19 activity and should hence be considered with similar 
caution.
Patients should not consume food or beverages containing the fruit or juice from grapefruits 
pomegranates, star fruit, papayas, or Seville oranges within 7 days before first dose of study drug 
or at anytime while on study.
Prophylactic use of anti-emetic, anti-nausea, and anti-diarrheal medications is encouraged and 
may be used prior to first dose of study drug (paclitaxel and MLN0128), and as needed 
throughout the study prior to each dosing and as clinically indicated per standard practice.  If 
dexamethasone is used, subjects need to be closely monitored for hyperglycemia and treated as 
needed per standard clinical practice and according to the guidelines in Section 7.2.7.
Myeloid growth factors, transfusions of blood and other blood products should not be used 
prophylactically prior to dosing of the study medications during Cycle 1 except as clinically 
indicated, but may be administered per standard clinical practice during the course of the study 
as needed.
Concurrent bisphosphonate use is allowed if bisphosphonate was initiated prior to the first 
administration of MLN0128.  Bisphosphonates should be given after Cycle 1 to minimize 
confounding factors which may contribute to potential drug-related toxicities. Renal function 
should be monitored closely in subjects receiving bisphosphonate therapy.  Subjects will be 
discontinued from the study if a new bisphosphonate needs to be started while on study for new 
metastatic bone lesions.
Other medications considered necessary for the subject’s safety and well-being may be given at 
the discretion of the Investigator.  Any concomitant medications added or discontinued during 
the study should be recorded on the CRF.
7.5.11
Treatment Compliance
The importance of treatment compliance should be emphasized to the subject.  Subjects will be 
given enough MLN0128 to dose between visits as well as detailed instructions on how to take 
medications at home.  Subjects will be instructed to return all used and unused study drug 
containers at each study visit.  Subject compliance with the dosing regimen will be assessed by 
reconciliation of the used and unused study drug at each clinic visit.  The quantity dispensed, 
returned, used, lost, etc. will be documented by site personnel on the appropriate form.  The site 
personnel will clarify any discrepancies in drug accountability with the subject and treatment 
compliance should be verified before dispensing new study medication to the subject.
7.6
Investigational Product Accountability
The Principal Investigator (PI) or designee is responsible for maintaining accurate drug 
accountability records (including dates and quantities) of MLN0128 received, subjects to whom 


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IP is dispensed (subject-by-subject dose specific accounting), and IP lost or accidentally or 
deliberately destroyed.  The PI or designee must retain all unused or expired study supplies until 
the Millennium-designated CRA has confirmed the accountability data.
7.6.1
Return and Disposition of Clinical Supplies
Unused MLN0128 must be kept in a secure location until it can be reconciled by the 
Millennium-designated CRA.  The Millennium-designated CRA must account for all study drug 
in a formal reconciliation process prior to study drug destruction. Unused study drug may be 
destroyed on site, per the site’s standard operating procedures, but only after Millennium or its 
designee has granted approval for drug destruction.  All study drug destroyed on site must be 
documented.  Documentation must be provided to Millennium or its designee and retained in the 
PI’s study files.  If a site is unable to destroy study drug appropriately, the site can return unused 
study drug to Millennium’s designee upon request.  The return of study drug or study drug 
materials must be documented according to instructions provided by Millennium’s designee.
All study drug and related materials should be stored, inventoried, reconciled, and destroyed or 
returned according to applicable state and federal regulations and study procedures.
7.7
Dietary or Other Protocol Restrictions
No dietary restrictions will be imposed on study subjects other than avoiding the fruit and fruit 
juices outlined in Appendix B.
7.8
Efficacy and Safety Variables 
7.8.1
Efficacy and Safety Measurements Assessed
The Schedule of Events in the Synopsis (Section 2.1) describes the timing of required 
evaluations.
7.8.2
Safety Variables
Safety will be assessed by periodic physical examinations, 12-lead ECGs (see Section 7.8.2.1, 
clinical laboratory assessments, in-home monitoring of glucose levels via a glucometer and 
monitoring of AEs.
Any abnormal clinical laboratory test results determined to be clinically significant by the 
Investigator should be repeated (at the Investigator’s discretion) until the cause of the 
abnormality is determined, the value returns to baseline or to within normal limits, or the 
Investigator determines that the abnormal value is no longer clinically significant.
All clinical laboratory result pages should be initialed and dated by an Investigator, along with a 
comment regarding whether or not the result is clinically significant.
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF.


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Adverse events will be graded using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.
7.8.2.1
Acquisition of 12-Lead Electrocardiograms
All scheduled ECGs should be performed after the patient has rested quietly for at least 
5 minutes in a supine position. When the timing of ECG assessments coincides with a blood 
collection, the ECG should be obtained prior to the nominal time of the blood collection. In 
some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead 
placement as contributing to the ECG abnormality.
7.8.2.2
Review of 12-Lead Electrocardiograms
To ensure safety, a qualified individual at the site will review any clinically significant ECG 
abnormalities, including confirmation that the machine-estimates of the QTc are accurate using 
the appropriate QT correction formula.  In the event that a QTc value confirmed by the qualified 
reader is > 480 msec, an evaluation should be conducted to correct other possible causes (eg, 
electrolyte disturbance, concomitant medication, etc.).  A list of medications known to prolong 
QTc can be found at www.torsades.org and www.QTdrugs.org.  If done prior to protocol 
enrollment and if a repeat ECG meets eligibility requirements, the patient may enroll to the study 
upon review and agreement by the medical monitor.
7.8.2.3
Review of Clinically Significant Electrocardiographic Abnormalities
In the event that a QTc value confirmed by the qualified reader is > 500 msec for any ECG, the 
following will occur:

The sponsor’s medical monitor will be promptly notified.

MLN0128 should be interrupted and an evaluation should be conducted to correct other 
possible causes (eg, electrolyte disturbance, concomitant medication).

A formal consult by a cardiologist should be considered.  Additional ECGs may be 
performed at intervals that the treating physician deems clinically appropriate until 
repeated QTc measurements fall are below the threshold interval that triggered the repeat 
measurement.
The decision on whether to reinitiate MLN0128 treatment with or without dose reduction and 
additional monitoring in those patients who had asymptomatic prolonged QTc > 500 msec 
(Grade 3) that has reverted to an acceptable interval, have previously tolerated MLN0128, and 
appear to have benefitted from MLN0128 treatment with either disease control or response, will 
be agreed to by the investigator and the medical monitor on a case-by-case basis.


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8
ADVERSE EVENTS
8.1
   Definitions
8.1.1
   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.
8.1.2
   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.
8.1.3
   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 or subject was at risk of death at 
the time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 


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when, based on appropriate medical judgment, may jeopardize the patient or subject, 
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, effective date 14 June 2010.(12)  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.
8.2
   Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient or subject 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 8.3 for the period 
of observation).  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 8.1) must 
be reported (see Section 8.3 for the period of observation) by the investigator to the Millennium 
Department of Pharmacovigilance or designee (contact information provided below).  This 
should be done by faxing the SAE Form within 24 hours after becoming aware of the event.  The 
SAE Form, created specifically by Millennium, will be provided to each clinical study site.  A 
sample of the SAE Form may be found in the Study Manual.  Follow-up information on the SAE 


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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
Cognizant
United States and Canada
Toll-Free Fax #: 1-800-963-6290
Email: TakedaOncoCases@cognizant.com
All Other Countries (Rest of World)
Fax #: 1-202-315-3560
Email: TakedaOncoCases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or later 
than planned).  For both serious and nonserious AEs, the investigator must determine both the 
intensity of the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE, 
Version 4.0.  The criteria are provided in the Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
related or not related to this question:  Is there a reasonable possibility that the AE is associated 
with the study drug?
8.3
   Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from administration of the first dose of study drug through 30 days 
after the administration of the last dose of study drug and recorded in the CRFs.
Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first dose of study 
drug, but will not be recorded in the CRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days after the 


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administration of the last dose of study drug and recorded in the CRF.  After this period, 
only related SAEs must be reported to the Millennium Department of Pharmacovigilance 
or designee.  SAEs should be monitored until they are resolved or clearly determined to 
be due to a patient’s stable or chronic condition or intercurrent illness(es).
8.4
   Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  The 
sponsor must also be contacted immediately by faxing a completed Pregnancy Form to the 
Millennium Department of Pharmacovigilance or designee (see Section 8.2).  The pregnancy 
must be followed for the final pregnancy outcome.
If a female partner of a male subject becomes pregnant during the male subject’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome.


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10
STUDY PROCEDURES
10.1
Screening and Baseline Assessments
An ICF must be obtained before any study-specific screening evaluations are performed and 
should be documented in the subject’s medical chart.
The following evaluations and procedures will be performed within 28 days prior to the first 
study drug administration (Cycle 1 Day 1):

Signed informed consent form for the Health Insurance of Portability and Accountability 
Act (HIPAA)

Medical history (including demographics and prior cancer therapy)

Concomitant medications

Radiological assessments: CT (with contrast) or MRI scans of chest, abdomen and/or 
pelvis (the method used for a subject [CT or MRI] must be the same throughout the 
study)

Tumor markers (eg, cancer antigen [CA]125, prostate-specific antigen [PSA], CA19-9, 
CA27.29, CA15.3 and carcinoembryonic antigen [CEA]) should be obtained within 4 
weeks prior to first dose

ECHO or MUGA
The subject must have discontinued all prior therapies according to the exclusion criteria and will 
have the following evaluations and procedures performed within 14 days prior to the first 
administration of study drug (Cycle 1 Day 1):

Complete physical examination including height, weight, vital signs and ECOG 
performance status (see Appendix A)

Concomitant medications

Laboratory assessments
o Hematology: complete blood count (CBC) with differential, hemoglobin, 
hematocrit, and platelet count
o HbA1c
o Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, lactate 
dehydrogenase (LDH), total bilirubin, direct bilirubin, total protein, sodium, 
potassium, chloride, bicarbonate, calcium, phosphate, magnesium, and fasting 
serum glucose.
o Coagulation: PT/INR, PTT
o Fasting serum lipid profile: total cholesterol, high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides
o Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted


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o Serum pregnancy for females of child-bearing potential only

12 -lead ECG (see Section 7.8.2.1)

Archival tumor tissue (either paraffin blocks or a minimum of 10 unstained slides of 
archival tumor tissue for assessment of predictive/prognostic markers.  Archival tumor 
tissues can be collected after the subject begins study drug treatment, if extra time is 
needed to locate the specimens).

Tumor tissue biopsy only on subjects who have tumor tissue that is accessible for biopsy 
per the Investigator and who have signed the consent for tumor biopsy (see Tumor 
Biopsy Laboratory manual).  This procedure can be done pre-dose on Cycle 1 Day 1, if it 
is not done during screening.
10.2
Treatment Visit(s)
If the subject meets all inclusion/exclusion criteria after the screening visit(s), the site will fax in 
the Subject Registration Form along with subject eligibility supporting documents to obtain a 
subject number and treatment cohort.  Once the site receives the assigned subject number and 
treatment cohort, the subject will start paclitaxel 80 mg/m2 intravenously (IV) weekly on Days 1, 
8 (±1 day), and 15 (±1 day) of every 28-day cycle in combination with MLN0128 administered 
QDx3d QW or via alternate dosing schedules (such as QDx5d QW) of a the 4- week cycle. Prior 
to Amendment 1, on days when weekly paclitaxel is administered (Days 1, 8 [±1 day], and 15 
[±1 day] of every 28-day cycle), MLN0128 was to be administered in the clinic within 30 
minutes of the completion of paclitaxel infusion.  Upon implementation of Amendment 1, 
MLN0128 will be administered approximately 24 hours following paclitaxel infusion. If 
paclitaxel dosing is altered ±1 day, MLN0128 administration should also be altered accordingly.
The subject should not take MLN0128 at home on the days of the clinic visits.  Subjects with 
HER2+ cancers in Arm B of the expansion phase will start trastuzumab weekly prior to the 
administration of paclitaxel on the days when weekly paclitaxel is administered.  On Day 22 
(±1 day) when paclitaxel is not administered, MLN0128 will be administered alone for subjects 
receiving MLN0128P and within 30 minutes of the completion of trastuzumab for subjects 
receiving MLN0128PH.  The subject should not have anything by mouth (eat or drink except 
water) after midnight prior to the clinic visits when blood draws for fasting glucose or fasting 
lipid profile will be required.  The subject will be given a glucometer to monitor daily pre-dose 
fasting glucose levels at home throughout the study.  Subjects will be instructed to notify the 
study staff immediately with any abnormal readings (ie, fasting blood glucose ≥140 mg/dL).
10.2.1
Cycle 1
10.2.1.1
Cycle 1 Week 1
10.2.1.1.1 Cycle 1 Day1
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:


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The following assessments will be repeated if they were done more than 3 days prior to Cycle 1 
Day 1:

Complete physical examination including weight, vital signs and ECOG performance 
status (see Appendix A)

12 -lead ECG (see Section 7.8.2.1)

Laboratory assessments
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted
o
Serum or urine pregnancy for females of child-bearing potential only
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting serum glucose
(Electrolyte levels should be corrected as needed prior to paclitaxel or 
trastuzumab dosing.)

Concomitant medications

Assessments of AEs
Paclitaxel and Trastuzumab Administration
Prior to Amendment 1 MLN0128 was to be administered within 30 minutes of completion of 
paclitaxel infusion. Upon implementation of Amendment 1, MLN0128 will be administered 
approximately 24 hours following paclitaxel infusion.  Once Amendment 1 was implemented at 
a given site, all active patients at that site converted to this new timing at the start of the next 
cycle.

Administration of paclitaxel for subjects receiving MLN0128P if results of hematology, 
CHEM-7 (BUN, creatinine, sodium, potassium, chloride, bicarbonate, and fasting serum 
glucose) and liver function tests (LFTs: ALT, AST, alkaline phosphatase, total bilirubin,
and direct bilirubin) are acceptable

Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7, and LFTs are acceptable
Procedures after Paclitaxel Administration:

Plasma PK samples will be obtained for subjects in the dose escalation phase prior to 
determination of the MTDMLN0128P: immediately at end of paclitaxel infusion (EOPI and 
pre-MLN0128 dose) and at 0.5 (±15 min) hour, 1 hour (±15 min), 2 hours (±30 min), 
4 hours (±30 min), and 6 hours (±30 min) (see Pharmacokinetic Laboratory Manual).

Assessments of AEs

Concomitant medications


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
Tumor biopsy for PD evaluation, if not done within 2 weeks prior to first dose
10.2.1.1.2 Cycle 1 Day 2
Subjects in the expansion phase are not required to return to clinic on this day. Subjects will take 
study medication at home per instructions.
The following assessments/procedures will be performed for subjects in the dose escalation 
phase.
Assessments prior to MLN0128 dosing:

PK sample for 24 hours (±2 hours) after Cycle 1 Day 1 dosing only for subjects 
participating in the dose escalation phase of the study (see Pharmacokinetic Laboratory 
Manual)

Fasting serum blood glucose

Assessments of AEs

Concomitant medications
MLN0128 Administration:

Administer MLN0128 orally in clinic 24 hours after paclitaxel administration (subjects in 
the expansion phase will take MLN0128 at home per instructions).
Procedure(s) after MLN0128 dosing:

Blood sampling for PK assessments only for subjects participating in the dose escalation 
phase prior to determination of the MTDMLN0128P: at 0.5 hour (±15 min), 1 hour 
(±15 min), 2 hours (±30 min), 4 hours (±30 min), and 6 hours (±30 min) post-MLN0128
dose 

Fasting blood glucose at 1 (±15 min) hour post-MLN0128 dose

ECG at 4 (±15 min) hours post-MLN0128 dose (see Section 7.8.2.1)

Dispense MLN0128 and provide dosing instructions to the subject.  Provide the subject 
with an in-home glucometer; train the subject on how to use the glucometer and instruct 
them to collect a daily pre-dose fasting glucose level every morning and to contact the 
site if a value is abnormal.  The early detection and treatment of hyperglycemia has been 
key in managing this drug-related AE effectively in previous human studies with 
MLN0128.  Each institution should decide an abnormal fasting glucose level (ie, 
≥140 mg/dL) where treatment and close monitoring of hyperglycemia might be required.
10.2.1.2
Cycle 1 Week 2 (Cycle 1 Day 8±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Symptom-directed physical examination including weight, vital signs, and ECOG 
performance status (see Appendix A)


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
12 -lead ECG (see Section 7.8.2.1)

Laboratory assessments
o
Hematology: CBC with differential, hematocrit, platelet count, and hemoglobin
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium, and fasting serum glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycle 1 Day 8±1)

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, 
CHEM-7, and LFTs are acceptable

Administration of trastuzumab and paclitaxel respectively for subjects receiving 
MLN0128PH if results of CBC, CHEM-7, and LFTs are acceptable
MLN0128 Administration (Cycle 1 Day 9±1):

Administer MLN0128 approximately 24 hours following paclitaxel infusion.
Procedure(s) after MLN0128 dosing:

Tumor biopsy for PD evaluation 3 hr ±1 hr post-MLN0128 dose (any day between Days 
9-16)

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.2.1.3
Cycle 1 Week 3 (Cycle 1 Day 15±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Symptom directed physical examination including weight, vital signs and ECOG 
performance status (see Appendix A)

12 -lead ECG (see Section 7.8.2.1)


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
Laboratory assessments
o
Hematology: CBC with differential, hematocrit, platelet count, and hemoglobin
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting glucose (electrolyte 
levels should be corrected as needed prior to paclitaxel or trastuzumab dosing)
o
Coagulation: PT/INR, PTT
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycle 1 Day 15±1)

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, 
CHEM-7, and LFTs are acceptable

Administration of trastuzumab and paclitaxel respectively for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Cycle 1 Day 16±1):

Administer MLN0128 approximately 24 hours following paclitaxel infusion.
Procedure(s) after MLN0128 dosing:

Tumor biopsy for PD evaluation 3 hr ±1 hr post-MLN0128 dose (any day between 
Days-9-16)

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.2.1.4
Cycle 1 Week 4 (Cycle 1 Day 22±1)
Assessments prior to MLN0128 dosing for subjects receiving MLN0128P or prior to 
trastuzumab dosing for subjects receiving MLN0128PH (note, subjects will not receive 
paclitaxel at this visit):

Symptom directed physical examination including weight, vital signs, and ECOG 
performance status (see Appendix A)

12 -lead ECG (see Section 7.8.2.1)


MLN0128
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
Laboratory assessments
o
Hematology: CBC with differential, hematocrit, platelet count, and hemoglobin
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting glucose (electrolyte 
levels should be corrected as needed prior to MLN0128 or trastuzumab dosing)
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11) 

Administration of trastuzumab for subjects receiving MLN0128PH
MLN0128 Administration

Administer MLN0128 (after completion of trastuzumab infusion for subjects receiving 
MLN0128PH)
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.2.2
Cycle 2
10.2.2.1
Cycle 2 Week 1 (Cycle 2 Day 1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Complete physical examination including weight, vital signs and ECOG performance 
status (see Appendix A)

12 -lead ECG (see Section 7.8.2.1)

Laboratory assessments
o
Hematology: CBC with differential, hematocrit, platelet count, and hemoglobin
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting glucose (electrolyte 
levels should be corrected as needed prior to paclitaxel or trastuzumab dosing)


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o
Coagulation: PT/INR, PTT
o
Fasting serum lipid profile: total cholesterol, HDL-C, LDL-C, triglycerides
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycle 2 Day 1±1)

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel respectively for subjects receiving 
MLN0128PH if results of CBC, CHEM-7, LFTs, and coagulation (PT/INR and PTT) are 
acceptable

Plasma PK samples will be obtained for subjects in the dose escalation phase prior to 
determination of the MTDMLN0128P: immediately at EOPI and pre-MLN0128 dose (see PK 
Laboratory Manual)
Procedure(s) after Paclitaxel Administration:

Blood sampling for PK assessments only for subjects participating in the dose escalation 
phase of the study at 0.5 hour (±15 min), 1 hour (±15 min), 2 hours (±30 min), 4 hours 
(±30 min) and 6 hours (±30 min) after the dosing (see PK Laboratory Manual)

Assessments of AEs

Concomitant medications

Return the glucometer to the subject for continued daily fasting glucose monitoring
10.2.2.2
Cycle 2 Week 1 (Cycle 2 Day 2)
Subjects in the expansion phase are not required to return to clinic on this day. Subjects will take 
study medication at home per instructions.
The following assessments/procedures will be performed for subjects in the dose escalation 
phase:
Assessments prior to MLN0128 dosing:

PK sample at pre-dose


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
Fasting blood glucose 

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications
Administer MLN0128 orally in clinic.
Procedure(s) after MLN0128 dosing:

Blood sampling for PK assessments only for subjects participating in the dose escalation 
phase prior to determination of the MTDMLN0128P : at 0.5 hour (±15 min), 1 hour (±15 
min), 2 hours (±30 min), 4 hours (±30 min), and 6 hours (±30 min) post-MLN0128 dose 

Fasting blood glucose at 0.5 hour (±15 min)

Dispense MLN0128 and provide dosing instructions to the subject.
10.2.2.3
Cycle 2 Weeks 2 and 3 (Cycle 2 Days 8±1 and 15±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination 

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting glucose (electrolyte 
levels should be corrected as needed prior to paclitaxel or trastuzumab dosing)
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11) 
Paclitaxel and Trastuzumab Administration (Cycle 2 Days 8±1 and 15±1)

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable


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MLN0128 Administration (Cycle 2 Days 9±1 and 16±1)

Administer MLN0128 approximately 24 hours following paclitaxel infusion.
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring 

Dispense MLN0128 and provide dosing instructions to the subject 
10.2.2.4
Cycle 2 Week 4 (Cycle 2 Day 22±1)
Assessments prior to MLN0128 dosing for subjects receiving MLN0128P or prior to 
trastuzumab dosing for subjects receiving MLN0128PH (note, subjects will not receive 
paclitaxel or trastuzumab at this visit):

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination 

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting glucose (electrolyte 
levels should be corrected as needed prior to MLN0128 dosing)
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11) 

Administration of trastuzumab for subjects receiving MLN0128PH
MLN0128 Administration

Administer MLN0128 (after completion of trastuzumab infusion for subjects receiving 
MLN0128PH)
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring 

Dispense MLN0128 and provide dosing instructions to the subject 


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10.2.3
Cycle 3 and Cycle 4
10.2.3.1
Cycles 3 and 4 Week 1 (Cycles 3 and 4 Day 1±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Complete physical examination including weight, vital signs and ECOG performance 
status (see Appendix A)

Tumor radiological assessments (prior to C3D1):  CT (with contrast) or MRI scans of 
chest, abdomen, and/or pelvis should be performed approximately after 2 cycles of 
therapy within 7 days prior to C3D1.  A confirmatory scan should be performed at 
approximately 4 weeks from the previous scan for all subjects with an objective response 
of ≥ PR.  The method (CT or MRI) used to assess tumor response in a subject must be the 
same throughout the study

C3D1: Tumor markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA)

C4D1 (±7days): ECHO/MUGA for subjects receiving MLN0128PH only

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and overnight fasting glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)
o
PTT and PT/INR
o
HbA1c (should be performed on Day 1 every 3 months starting C4D1)
o
Fasting serum lipid profile: total cholesterol, HDL-C, LDL-C, triglycerides
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Day 1 of Cycles 3 and 4):

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7, LFTs, and PT/INR and PTT are acceptable


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
Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Day 2 of Cycles 3 and 4):

Administer MLN0128 approximately 24 hours following paclitaxel infusion.
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring 

Dispense MLN0128 and provide dosing instructions to the subject 
10.2.3.2
Cycles 3 and 4 Week 2 (Cycles 3 and 4 Day 8±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination 

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting serum glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycles 3 & 4 Day 8±1):

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Cycles 3 & 4 Day 9±1):

Administer MLN0128 approximately 24 hours following paclitaxel infusion.
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring 

Dispense MLN0128 and provide dosing instructions to the subject 


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10.2.3.3
Cycles 3 and 4 Week 3 (Cycles 3 and 4 Day 15±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination 

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and overnight fasting glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11) 
Paclitaxel and Trastuzumab Administration (Cycles 3 & 4 Day 15±1):

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel respectively for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Cycles 3 & 4 Day 16±1):

Administer MLN0128 approximately 24 hours following paclitaxel infusion
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject


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10.2.3.4
Cycles 3 and 4 Week 4 (Cycles 3 and 4 Day 22±1)
Assessments prior to MLN0128 dosing alone for subjects receiving MLN0128P or prior to 
trastuzumab dosing for subjects receiving MLN0128PH (note, subjects will not receive 
paclitaxel at this visit):

Symptom directed physical examination including weight, vital signs and ECOG 
performance status (see Appendix A)

Laboratory assessments
o
Hematology: CBC with differential, hematocrit, platelet count, and hemoglobin
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting glucose (electrolyte 
levels should be corrected as needed prior to MLN0128 or trastuzumab dosing)
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Assessments of adverse events including a review of the daily FBG readings from the 
glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)

Administration of trastuzumab for subjects receiving MLN0128PH
MLN0128 Administration
Administer MLN0128 (after completion of trastuzumab infusion for subjects receiving 
MLN0128PH).
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.2.4
Cycle 5 and Onward
10.2.4.1
Cycle 5 and Onward Week 1 (Cycle 5 and onward Day 1±1 
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Complete physical examination including weight, vital signs and ECOG performance 
status (see Appendix A)


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
Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and overnight fasting glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)
o
Coagulation: PTT and PT/INR 
o
Fasting serum lipid profile: total cholesterol, HDL-C, LDL-C, triglycerides
o
HbA1c
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Tumor radiological assessments: CT (with contrast) or MRI scans of chest, abdomen 
and/or pelvis should be performed for response assessment approximately every 2 cycles 
(±7 days) starting from C3D1.  A confirmatory scan should be performed approximately 
4 weeks from the previous scan for all subjects with an objective response of ≥ PR.  The 
method (CT or MRI) used to assess tumor response in a subject must be the same 
throughout the study

Tumor markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA) should also be 
performed approximately every 2 cycles (±7 days) starting from C3D1

ECHO/MUGA every 3 cycles (±7 days) starting from Cycle 4 Week 1 for subjects 
receiving MLN0128PH only

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycle 5 and onward Day 1):

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Cycle 5 and onward Day 2):

Administer MLN0128 approximately 24 hours following paclitaxel infusion
Procedure(s) after MLN0128 dosing:


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
Return the glucometer to the subject for continued daily fasting glucose monitoring 

Dispense MLN0128 and provide dosing instructions to the subject
10.2.4.2
Cycle 5 and Onward Week 2 (Cycle 5 and Onward Day 8±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting serum glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycle 5 and onward Day 8±1):

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Cycle 5 and onward Day 9±1):

Administer MLN0128 approximately 24 hours following paclitaxel infusion
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.2.4.3
Cycle 5 and Onward Week 3 (Cycle 5 and Onward Day 15±1)
Assessments prior to paclitaxel dosing for subjects receiving MLN0128P or trastuzumab dosing 
for subjects receiving MLN0128PH:

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination


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
Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting serum glucose
(electrolyte levels should be corrected as needed prior to paclitaxel or trastuzumab 
dosing)

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Paclitaxel and Trastuzumab Administration (Cycle 5 and onward Day 15±1): 

Administration of paclitaxel for subjects receiving MLN0128P if results of CBC, CHEM-
7 and LFTs are acceptable

Administration of trastuzumab and paclitaxel, respectively, for subjects receiving 
MLN0128PH if results of CBC, CHEM-7 and LFTs are acceptable
MLN0128 Administration (Cycle 5 and onward Day 16±1):

Administer MLN0128 approximately 24 hours following paclitaxel infusion
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.2.4.4
Cycle 5 onward Week 4 (Cycle 5 onward Day 22±1)
Please note this clinic visit is only required for subjects receiving MLN0128PH
Assessments prior to trastuzumab dosing for subjects receiving MLN0128PH (note, subjects will 
not receive paclitaxel at this visit):

Weight, vital signs and ECOG performance status (see Appendix A)

Symptom directed physical examination 

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and fasting serum glucose
(electrolyte levels should be corrected as needed prior to trastuzumab dosing)

Assessments of AEs including a review of the daily FBG readings from the glucometer

Concomitant medications


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
Conduct drug accountability on the returned empty bottles and unused medications.  
Compliance of the dosing will be monitored and documented (see Section 7.5.11)
Prior to MLN0128 dosing: 

Administration of trastuzumab 
MLN0128 Administration:
Administer MLN0128 after completion of trastuzumab infusion for subjects receiving 
MLN0128PH
Procedure(s) after MLN0128 dosing:

Return the glucometer to the subject for continued daily fasting glucose monitoring

Dispense MLN0128 and provide dosing instructions to the subject
10.3
Termination Visit
The following assessments must occur within 30 days after the last administration of MLN0128,
paclitaxel, or trastuzumab, whichever is discontinued last:

Complete physical examination including weight, vital signs and ECOG performance 
status (see Appendix A)

12 -lead ECG (see Section 7.8.2.1)

Laboratory assessments
o
Hematology: CBC with differential, hemoglobin, hematocrit, and platelet count
o
HbA1c
o
Chemistry (fasting): BUN, creatinine, ALT, AST, alkaline phosphatase, LDH, 
total bilirubin, direct bilirubin, total protein, sodium, potassium, chloride, 
bicarbonate, calcium, phosphate, magnesium and overnight fasting glucose
o
Coagulation: PTT and PT/INR
o
Fasting serum lipid profile: total cholesterol, HDL-C, LDL-C, triglycerides
o
Urinalysis: macroscopic assessment of the amount of protein, glucose, white 
blood cells and blood if they are present (record levels as available) and 
microscopic analysis if an abnormality is noted.  Microscopic urinalysis will also 
be performed along with a 12-hour urine collection and spot urine electrolytes, 
protein and creatinine and serum chemistry at any time when the serum creatinine 
is ≥ Grade 1 according to NCI CTCAE version 4.0.

Tumor radiological assessments and tumor markers (eg, CA125, PSA, CA19-9, CA27.29, 
CA15.3, and CEA) for subjects who have not previously demonstrated disease 
progression in the study unless completed within the previous 4 weeks: CT (with 
contrast) or MRI scans of chest, abdomen and pelvis. A confirmatory scan should be 
performed at approximately 4 weeks from the previous scan for all subjects with an 
objective response of ≥ PR.  The method (CT or MRI) used to assess tumor response in a 
subject must be the same throughout the study


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
ECHO/MUGA for subjects receiving MLN0128PH only

Assessments of AEs 

Concomitant medications

Conduct drug accountability on the returned empty bottles and unused medications


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11
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
This section outlines the statistical analysis strategy and procedures for the study.  Specific 
details of the primary and key secondary analyses will be provided in the Statistical Analysis 
Plan (SAP).  If, after the study has begun, but prior to the final analysis, important changes are 
made to the protocol that affect principal features of the primary or key secondary analyses, then 
the protocol and/or SAP will be amended, as appropriate.  Any other changes made to the 
planned analyses after the protocol and SAP have been finalized, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study.  
Post hoc exploratory analyses will be clearly identified in the CSR.
11.1
Analysis Endpoints
The safety and efficacy endpoints to be evaluated are listed below, followed by descriptions of 
the derivations of selected endpoints.
11.1.1
Primary Endpoints
11.1.1.1
Dose Escalation Phase:
The maximum tolerated dose of MLN0128 will be determined when administered orally 
QDx3d QW and/or via alternate dosing schedules (such as QDx5d QW) in combination with 
weekly paclitaxel in subjects with advanced solid malignancies.  The MTD of each dosing 
schedule is defined as the highest dose level of MLN0128 administered at which no more than 
1 out of 6 evaluable subjecting experiencing DLT during the first treatment cycle.  The rate of 
DLT will be determined from the occurrence of adverse events which meet the criteria in 
Section 7.2.1.
11.1.1.2
Expansion Phase:
The objective response rate will be estimated for each tumor histology cohort studied in the 
expansion phase.  Arm A will consist of HER2– cancer subjects receiving MLN0128P; Arm B 
will consist of HER+ cancer subjects receiving MLN0128P plus weekly trastuzumab 
(MLN0128PH).  The objective response rate will be based on the subject’s best overall tumor 
response documented during the course of protocol therapy.  Objective response includes CR and 
PR and will be determined based on RECIST (version 1.1).  The duration of objective response 
will be evaluated for subjects who achieve CR or PR.
11.1.2
Secondary Endpoints
The plasma pharmacokinetics of MLN0128 in combination with paclitaxel will be determined 
from selected subjects based on the PK parameters listed below.  The plasma pharmacokinetics 
of paclitaxel in combination with MLN0128 will be evaluated in a similar manner.  Plasma 
samples for PK analysis will be collected at the times specified in the Schedule of Events.

Maximum plasma concentration (Cmax)


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
Minimum plasma concentration (Cmin)

Time of maximum plasma concentration (Tmax)

Plasma half-life (t½)

Area under the plasma concentration-time curve from time zero to infinity 
(AUC0-∞), zero to last dose (AUC0-last), and %AUC extrapolated

The additional intravenous PK parameters, CL, and Vss will be estimated for paclitaxel
11.1.3
Safety and Tolerability Endpoints
Safety and tolerability of MLN0128P and MLN0128PH will be assessed in each study phase (if 
applicable) based on the following:

Incidence, duration, and severity of treatment-emergent adverse events, including dose-
limiting toxicity (see Section 7.2.1), serious adverse events, adverse events resulting in 
permanent discontinuation of protocol treatment, and deaths within 30-days of the last 
dose of protocol treatment

Changes in laboratory test results including chemistry and hematology

Changes in vital signs including blood pressure, pulse, and temperature

Changes in electrocardiogram results
11.2
Analysis Populations
11.2.1
Safety Analysis
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data.  The 
ASaT population consists of all enrolled subjects who receive at least 1 dose of MLN0128.  The 
safety data from the dose escalation phase will be summarized by dose cohort; and by tumor 
histology cohort for the expansion phase.
For purposes of defining the MTD and/or expansion phase recommended dose of MLN0128, 
subjects will be evaluated according to the actual starting dose of MLN0128 during the first 
treatment cycle.  For most subjects, this will be the dose cohort to which they were assigned.  
Subjects who receive ≥ 75% of the planned MLN0128 doses in Cycle 1 will be considered to 
have sufficient safety data/follow-up to support dose escalation.  Subjects who withdraw from 
study before receiving at least 75% of the planned MLN0128 doses in the first cycle of treatment 
for reasons unrelated to study drug toxicity will be considered to have inadequate data to support 
dose escalation.  In such cases, replacement subjects may be enrolled to receive the same starting 
dose of MLN0128 as the subjects who withdraw prematurely.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of study 
drug is required for inclusion in the analysis of a specific safety parameter.  To assess change 
from baseline, a baseline measurement is also required.


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11.2.2
Efficacy Analysis
The Full Analysis Set (FAS) population will serve as the primary population for the analysis of 
tumor response and other efficacy-related data.  Subjects will be excluded for FAS for the 
following reasons:

Failure to receive at least 1 dose of MLN0128

No post-baseline endpoint data subsequent to at least 1 dose of study drug

Lack of baseline data for those analyses that require baseline data
Subjects will be grouped in the FAS population according to tumor histology.  A supportive 
analysis using the Per-Protocol population will be performed for the tumor response analysis.  
The Per-Protocol population excludes subjects due to important deviations from the protocol that 
may substantially affect the results of the primary analysis.  The final determination on protocol 
violations, and thereby the composition of the Per-Protocol population, will be made prior to 
locking the clinical database and final analysis and will be documented in a separate memo.
11.3
Statistical Methods
11.3.1
Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events, DLTs, laboratory values, electrocardiogram results, and vital signs.
The observed DLT rate will be calculated by the crude proportion of subjects who experience 
DLT during the first cycle of protocol treatment.  Multiple concurrent adverse events leading to 
DLT will be considered a single DLT.  The estimate of the DLT rate will be accompanied by a 
2-sided 95% exact binomial confidence interval.  The relationship between the dose of 
MLN0128 and probability of DLT will be assessed by fitting various regression models such as 
Emax, logistic and exponential model shapes.
Adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Treatment-emergent adverse events are defined as adverse 
events that start on or after the first administration of protocol treatment and within 30 days of 
the last administration.  Adverse events will be summarized by the number and percentage of 
subjects who experienced the event, according to system organ class and preferred term.  A 
subject reporting multiple cases of the same adverse event will be counted once within each 
system organ class and similarly counted once within each preferred term.  Unless specified 
otherwise, the denominator for these calculations will be based on the number of subjects in each 
dose cohort who receive at least 1 administration of MLN0128, irrespective of the total number 
of doses or treatment cycles administered.  These conventions will be appropriately modified to 
calculate AE incidence rates separately for each cycle that study therapy is administered.  AE 
incidence rates may also be calculated based on other measures of subject exposure (eg, total 


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number of treatment cycles administered).  AEs will also be summarized by NCI-CTCAE 
version 4.0 severity, grade, and by relationship to each treatment administered.  Additional 
summaries may also be provided for SAEs, and events resulting in the permanent discontinuation 
of protocol therapy.  All AEs will be included in individual subject listings.
The changes in hematology, chemistry, and other laboratory values will be summarized 
descriptively for each scheduled and unscheduled protocol assessment time point.  Changes will 
be calculated relative to the values collected at baseline and on the first day of each cycle of 
treatment.  The incidence of grade 3 and 4 hematological toxicities (including neutropenia, 
thrombocytopenia, and anemia) will be provided by treatment cycle and across all treatment 
cycles.  The toxicity grades for laboratory tests will be based on NCI-CTCAE version 4.0 
criteria.  The use of blood transfusions (platelets, red blood cells) and/or growth factor support 
will be reported.  Similar analyses will be done for selected chemistry tests (including liver and 
renal function tests).  Subject listings of all laboratory data collected during the study will be 
presented.  Laboratory values outside normal limits will be identified in the subject listings and 
will include flags for high and low values.
Vital sign results (blood pressure, pulse, respirations, and temperature) will be summarized 
descriptively for each scheduled and unscheduled protocol time point.  Changes will be 
calculated relative to the assessments at baseline and on the first day of each cycle of therapy.
11.3.2
Efficacy Analysis
The efficacy analysis will be conducted for the FAS and Per-Protocol populations defined in 
Section 11.2.2.  The results of this analysis will be presented by tumor histology cohort.
Objective Response Rate:
The objective response rate will be estimated for each tumor histology cohort in the expansion 
phase.  The estimate of the objective response rate will be calculated based on the maximum 
likelihood estimator (ie, crude proportion of subjects whose best overall response is CR or PR).  
The estimate of the objective response rate will be accompanied by 1-sided and 2-sided 95% 
exact binomial confidence intervals.
Duration of Objective Response:
The duration of objective response will be calculated for subjects who achieve CR or PR.  For 
such subjects, the duration of objective response is defined as the number of days from the start 
date of PR or CR (whichever response is achieved first) to the first date that progressive disease 
is objectively documented.  Disease progression will be determined by the Investigator using 
RECIST (version 1.1).  The duration of objective response will be right-censored for subjects 
who achieve CR or PR and meet 1 of the following conditions: 1) non-protocol anticancer 
treatment started before documentation of disease progression, 2) death or documented disease 


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progression after more than 1 missed disease assessment visit, or 3) alive and does not have 
documentation of disease progression before a data analysis cutoff date.  For such subjects, the 
duration of objective response will be right-censored according to Table 11.1 below.  These 
conventions are based on the May 2007 FDA Guidance for Industry, 
‘Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics’ 
(fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.
pdf).
The duration of objective response will be summarized descriptively using the Kaplan-Meier 
method.  The 50th percentile of the Kaplan-Meier distribution will be used to estimate the median 
response duration.
Table 11.1  
Date of Progression or Censoring for Duration of Response
Situation
Date of Progression or Censoring
Outcome
Non-protocol anti-cancer treatment 
started before death or documentation 
of disease progression or death
Date of last disease assessment prior to 
start of non-protocol anticancer treatment
Censored
Death or progression after more than 1 
missed disease assessment
Date of last disease assessment visit 
without documentation of disease 
progression that is before the first missed 
visit
Censored
Alive and without documentation of 
disease progression
Date of last disease assessment
Censored
Death or disease progression between 
planned disease assessments
Date of death or first disease assessment 
showing disease progression, whichever 
occurs first 
Progressed
Death before first disease assessment
Date of death
Progressed
11.4
Sample Size Determination
11.4.1
Dose Escalation Phase
Cohorts of 3 to 6 subjects will be enrolled in each MLN0128 dose cohort based on a standard 
phase 1 sequential dose escalation scheme.  Each subject will participate in only 1 dose cohort.  
The total number of subjects to be enrolled in the dose escalation phase of the study is dependent 
upon the observed safety profile, which will determine the number of subjects per dose cohort, as 
well as the number of dose escalations required to achieve the MTD.
11.4.2
Expansion Phase
After the MTD of MLN0128 has been identified, 2 cohorts of subjects will be enrolled in 
parallel:


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
Arm A will consist of approximately 30 HER2– cancer subjects receiving MLN0128P

Arm B will consist of approximately 30 HER2+ cancer subjects receiving MLN0128PH.  
Up to 3 subjects will be enrolled initially in Arm B and observed for one cycle prior to 
enrolling additional subjects into this arm.
The approximate sample size of 30 subjects in Arms A and B is based on following 
considerations:  An experimental regimen that results in an objective response rate of 1% or less 
is considered to have insufficient activity to warrant further study.  An objective response rate of 
15% or greater is considered sufficient to warrant further study of the regimen. Up to 30 subjects 
in each arm will provide greater than 90% power to detect a statistically significant difference 
between the uninteresting and interesting objective response rates based on the exact 1-sample 
binomial test and 1-sided significance level of 5%.
11.5
Interim Analysis and Early Stopping Guidelines
Safety will be monitored throughout the trial.  Dose escalation will proceed according to the dose 
escalation scheme described in Section 7.2.3.  If any significant safety issues arise, the Sponsor 
will be notified and if necessary, a decision to modify or terminate the trial (or 1 of the cohorts) 
will be made.
All participating sites are required to provide DLT notification forms within 24 hours of learning 
of the event.  Additionally, site teleconferences between the Sponsor and all participating sites 
will be held approximately every 1 to 2 weeks during the dose escalation phase to discuss any 
suspected AEs/DLTs that have occurred at each cohort.  Participating Investigators and the 
Sponsor’s Medical Monitor will review study drug-related toxicities from the current cohort 
during the site teleconferences before initiating enrollment into the next planned dose cohort.
11.6
Changes in the Conduct of the Study or Planned Analyses
Only Millennium may modify the protocol.  Any change in study conduct considered necessary 
by the PI will be made only after consultation with Millennium, who will then issue a formal 
protocol amendment to implement the change.  The only exception is when an Investigator 
considers that a subject’s safety is compromised without immediate action.  In these 
circumstances, immediate approval of the chairman of the IRB/EC must be sought, and the 
Investigator should inform Millennium and the full IRB/EC within 2 working days after the 
emergency occurs. 
With the exception of minor administrative or typographical changes, the IRB/EC must review 
and approve all protocol amendments.  Protocol amendments that have an impact on subject risk 
or the study objectives, or require revision of the ICF, must receive approval from the IRB/EC 
prior to their implementation.


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When a protocol amendment substantially alters the study design or the potential risks or burden 
to subjects, the ICF will be amended and approved by Millennium and the IRB/EC, and all active 
subjects must again provide informed consent.


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12
ETHICS
12.1
Institutional Review Board or Ethics Committee
Prior to initiating the study, the Investigator will obtain written confirmation that the Institutional 
Review Board (IRB) is properly constituted and compliant with all United States Food and Drug 
Administration (FDA) requirements and local regulations.  A copy of the confirmation from the 
IRB/EC will be provided to Millennium or its designee.  The Principal Investigator (PI) will 
provide the IRB/EC with all appropriate material, including the protocol, Investigator’s 
Brochure, the Informed Consent Form (ICF), and any other written information provided to the 
subjects, including all consent forms translated to a language other than the native language of 
the clinical site.  The study will not be initiated until appropriate IRB approval of the protocol, 
the ICF and all subject recruitment materials are obtained in writing by the PI and copies are 
received at Millennium or its designee.  The approval document should refer to the study by 
protocol title and Millennium, protocol number (if possible), identify the documents reviewed, 
and include the date of the review and approval.  Appropriate reports on the progress of the study 
should be made to the IRB/EC or REB and Millennium or its designee by the PI in accordance 
with applicable governmental regulations and in agreement with policy established by the 
IRB/EC and Millennium.
12.2
Ethical Conduct of Study
This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical 
Practice (GCP) according to International Conference on Harmonization (ICH) guidelines.  
Specifically, this study is based on adequately performed laboratory and animal experimentation; 
the study will be conducted under a protocol reviewed and approved by an IRB/EC; the study 
will be conducted by scientifically and medically qualified persons; the benefits of the study are 
in proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study do not find the hazards to outweigh the potential benefits; and each subject, 
or his/her legally authorized representative will provide written, informed consent before any 
study-related tests or evaluations are performed.
12.3
Subject Information and Informed Consent
A properly written and executed ICF, in compliance with the Declaration of Helsinki, ICH GCP 
and US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25 [a,b.], 
CFR 50.27, and CFR Part 56, Subpart A), HIPAA for the US only, and other applicable local 
regulations, will be obtained for each subject prior to entering the subject into the study.  The 
Investigator will prepare the ICF and HIPAA authorization and provide the documents to 
Millennium or its designee for approval prior to submission to the IRB.  Millennium and the 
IRB/EC must approve the documents before they are implemented.  If a subject is unable to sign 
the ICF and HIPAA authorization, a legal representative may sign for the subject.  The 


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Investigator will provide copies of the signed ICF to each subject (or the subject’s legal 
representative) and will maintain the original in the subject’s record file.


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13
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Prior to beginning the study, the PI at each site must provide to Millennium or its designee a 
fully executed and signed Form FDA 1572 and a Financial Disclosure Form.  All sub-
Investigators must be listed on Form FDA 1572.  Financial Disclosure Forms must also be 
completed for all sub-Investigators listed on the Form FDA 1572 who will be directly involved 
in the treatment or evaluation of research subjects in this study.
The study will be administered by and monitored by employees or representatives of 
Millennium.  CRAs will monitor each site on a periodic basis and perform verification of source 
documentation for each subject as well as other required review processes. Millennium’s 
designee will be responsible for the timely reporting of SAEs to appropriate regulatory 
authorities as required.


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14
CASE REPORT FORMS AND SOURCE DOCUMENTS
CRF data will be entered electronically for this study.  Millennium’s policy is that study data on 
the CRFs must be verifiable to the source data, which necessitates access to all original 
recordings, laboratory reports, and subject records. In addition, all source data should be 
attributable (signed and dated).  A CRA designated by Millennium will compare the eCRFs with 
the original source documents at the study site and evaluate the CRFs for completeness and 
accuracy.  Designated site personnel must complete the eCRFs as soon as possible after a subject 
visit, and the forms must be available for review at the next scheduled monitoring visit.  The 
Investigator must review and sign off on the completed eCRFs to verify their accuracy.


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15
STUDY MONITORING AND AUDITING
Qualified individuals designated by Millennium will monitor all aspects of the study according 
to GCP and standard operating procedures for compliance with applicable government 
regulations.  The PI agrees to allow these Millennium-designated CRAs direct access to the 
clinical supplies, dispensing, and storage areas and to the clinical files, including original 
medical records, of the study subjects, and, if requested, agrees to assist the Millennium-
designated CRAs.  The PI and staff are responsible for being present or available for consultation 
during routinely scheduled site visits conducted by Millennium or its designees.
Members of Millennium GCP Compliance Department or designees may conduct an audit of a 
clinical site at any time during or after completion of the study.  The PI will be informed if an 
audit is to take place and advised as to the scope of the audit.  Representatives of the FDA or 
other Regulatory Agencies may also conduct an audit of the study.  If informed of such an 
inspection, the PI should notify Millennium immediately.  The PI will ensure that the auditors 
have access to the clinical supplies, study site facilities, original source documentation, and all 
study files.


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16
RETENTION OF RECORDS
The PI must retain all study records required by Millennium and by the applicable regulations in 
a secure and safe facility.  The PI must notify Millennium of any change in the location, 
disposition or custody of the study files.  The PI/institution must take measures to prevent 
accidental or premature destruction of essential documents, that is, documents that individually 
and collectively permit evaluation of the conduct of a study and the quality of the data produced, 
including paper copies of study records (eg, subject charts) as well as any original source 
documents that are electronic as required by applicable regulatory requirements. 
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the U.S. or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP.  No records relating to this study should 
be disposed of without the written approval of Millennium.  It is the responsibility of Millennium
to inform the PI/institution as to when these documents no longer need to be retained.


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17
DISCLOSURE OF DATA
Subject medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited.
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare.
Data generated by this study must be available for inspection upon request by representatives of 
the U.S. FDA, national and local health authorities, Millennium and the IRB for each study site, 
if appropriate.


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18
REFERENCES
1.
Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends in 
Molecular Medicine 2007;13(10):433-42.
2.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nature Reviews. 
Cancer 2006;6(9):729-34.
3.
TORISEL Kit (temsirolimus) injection, for intravenous infusion only [package insert]. 
Philadelphia, PA: Wyeth Pharmaceuticals Inc (Pfizer); 2011.
4.
AFINITOR (everolimus) tablets for oral administration [package insert]. East Hanover, 
NJ: Novartis; 2011.
5.
O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR Inhibition 
Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt. Cancer Res 
2006;66(3):1500-8.
6.
Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, et al. mTOR 
complex 2 is required for the development of prostate cancer induced by Pten loss in 
mice. Cancer Cell 2009;15(2):148-59.
7.
Nardella C, Carracedo A, Alimonti A, Hobbs RM, Clohessy JG, Chen Z, et al. 
Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Science 
Signaling [Electronic Resource] 2009;2(55):ra2.
8.
Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety 
profile of mTOR inhibitors, a novel class of anticancer agents. Targeted Oncology 
2009;4(2):135-42.
9.
RAPAMUNE (sirolimus) Oral Solution and Tablets [package insert]. Philadelphia, PA: 
Pfizer; 2010.
10.
TAXOL® (paclitaxel) INJECTION [package insert]. Princeton, NJ: Bristol-Myers 
Squibb Company; 2011.
11.
Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 
2003.
12.
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.


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20
APPENDICES
20.1
Appendix A:  ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease 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


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20.2
Appendix B:  A LIST OF STRONG CYP3A4, CYP2C9 AND CYP2C19 
INDUCERS/INHIBITORS
ganfyd.org/index.php?title=Inhibitors_of_CYP3A4
medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp
Strong Inhibitors
Drugs
Fruits and Fruit Juices
indinavir
Star fruit & star fruit juice
nelfinavir
Pomegranates & pomegranate juice
ritonavir
Papaya & papaya juice
clarithromycin
Grapefruit & grapefruit juice
itraconazole
Seville oranges & seville orange juice  
ketoconazole
nefazodone
fluconazole
saquinavir
telithromycin
Inducers
carbamazepine
phenobarbitol
phenytoin
rifabutin
St. John’s wort
troglitazone
secobarbitol
rifampin


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20.3
Appendix C  New York Heart Association Classification of Cardiac Disease
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.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256. 


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MLN0128
Clinical Study Protocol INK128-003 Amendment 7
Confidential
105
study drug administration;
Now 
reads:
9.  For women of child-bearing potential, negative serum pregnancy test 
within 14 days prior to the first study drug administration and use of 
physician-approved method of birth control from 30 days prior to the first 
study drug administration to 90 days following the last study drug 
administration;
10.  Male subjects must be surgically sterile or must agree to use physician-
approved contraception during the study and for 90 days following the last 
study drug administration;
Section 2, Synopsis, also contains this change.
Purpose:  Update SAE reporting information to align with current procedures
The primary change occurs Section 8.2, Procedures for Recording and Reporting Adverse 
Events and Serious Adverse Events:
Formerly 
read:
SAE Reporting Contact Information – United States and Canada 
PPDI Pharmacovigilance
Fax:  888-488-9697
24-hour helpline:  800-201-8725
SAE Reporting Contact Information – Rest of World (except Central and 
South America)
PPDI Pharmacovigilance
Fax: +44 1223 374102
24-hour helpline:  +44(0)1223 374240
Now 
reads:
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-Free Fax #:  1-800-963-6290
Email:  TakedaOncoCases@cognizant.com
All Other Countries (Rest of World)
Fax #:  1-202-315-3560
Email:  TakedaOncoCases@cognizant.com
Purpose:  Correct typographical errors, grammar, punctuation, and formatting
These changes are not listed individually.


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
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 information or company confidential information. 
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.
Title: A Phase I, Open Label, Dose Escalation Study of Oral Administration of INK128 in 
Combination with Paclitaxel, with/without Trastuzumab, in Subjects with Advanced Solid 
Malignancies
NCT Number: NCT01351350
Protocol Approve Date: October 7, 2013


PPD


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................4
1. INTRODUCTION................................................................................................................6
1.1 Study Design...................................................................................................................6
1.2 Study Objectives.............................................................................................................6
2. POPULATIONS FOR ANALYSIS .....................................................................................8
2.1 All Subjects as Treated (ASaT) Population....................................................................8
2.2 Full Analysis Set (FAS) Population ...............................................................................8
2.3 Pharmacokinetics Population .........................................................................................8
2.4 Dose-Escalation Evaluable Population...........................................................................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...............................................................................................................10
5.4.1 Methods for Handling Missing Data .....................................................................10
5.4.2 Definition of Baseline Values................................................................................10
5.4.3 Windowing of Visits..............................................................................................10
5.5 Patient Disposition........................................................................................................10
5.6 Demographics and Baseline Disease Characteristics ...................................................11
5.6.1 Demographics........................................................................................................11
5.6.2 Medical History .....................................................................................................11
5.7 Treatments and Medications.........................................................................................12
5.7.1 Concomitant Medications......................................................................................12
5.7.2 Study Treatments...................................................................................................12
5.8 Efficacy Analyses.........................................................................................................12
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis...................................13
5.9.1 Pharmacokinetic Analyses.....................................................................................13
5.9.2 Pharmacodynamic Analyses..................................................................................15
5.9.3 Biomarker Analysis ...............................................................................................16
5.10 Safety Analyses ..........................................................................................................16
5.10.1 Adverse Events ....................................................................................................16
5.10.2 Laboratory Data...................................................................................................19
5.10.3 Vital Signs............................................................................................................19
5.10.4 Electrocardiograms..............................................................................................20
5.10.5 ECOG Performance Status ..................................................................................20
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL.......................................20
7. PROGRAMMING CONSIDERATIONS ..........................................................................21
7.1 Statistical Software.......................................................................................................21
7.2 Rules and Definitions ...................................................................................................21
7.2.1 Study Drug.............................................................................................................21
7.2.2 Study Day 1 ...........................................................................................................21


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
3
7.2.3 Study Day ..............................................................................................................21
7.2.4 Cycle 1 Day 1 ........................................................................................................21
7.2.5 Cycle k Day j..........................................................................................................22
7.2.6 Age at Screening....................................................................................................22
8. REFERENCES ...................................................................................................................22


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MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
5
Abbreviation or 
Term
Definition
SE
standard error
S6
ribosomal protein
T1/2
half-life
Tmax
time of maximum concentration
TEAEs
treatment emergent adverse events
WHO
World Health Organization


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
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 
addresses the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This is a phase 1, open-label study consisting of a dose-escalation phase in advanced solid 
malignancies to determine the MTD of oral administration of MLN0128 (QDx3dQW on a 
4-week cycle) or via alternate dosing schedules (such as 5 days on, 2 days off repeated 
weekly[QDx5d QW] or QW) in combination with an infusion of paclitaxel on Days 1, 8, 
and 15 of each cycle (MLN0128P), followed by an expansion phase at the MLN0128P 
MTD (MTDMLN0128P) ± trastuzumab in up to 25 additional subjects for further safety and 
preliminary efficacy. A cycle will be defined as 4 weeks.
Once the MTDMLN0128P is determined for each of the dosing schedules evaluated, an 
additional 6 subjects may be enrolled at the MTDMLN0128P for further safety and PK 
evaluation. A dose and schedule will be selected for the expansion phase which may enroll 
subjects into 2 arms in parallel:

Arm A will consist of HER2- cancer subjects receiving MLN0128P at the 
MTDMLN0128P

Arm B will consist of HER2+ cancer subjects receiving MLN0128P at the 
MTDMLN0128P plus weekly trastuzumab (MLN0128PH)
1.2   
Study Objectives
The primary objectives of the study are:

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) 
of MLN0128 when administered on a QDx3d QW schedule of a 4-week cycle or via 
alternate dosing schedules (such as 5 days on, 2 days off weekly [QDx5d QW]) in 


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MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
8
2.   
POPULATIONS FOR ANALYSIS
2.1   
All Subjects as Treated (ASaT) Population
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data.  
The ASaT population consists of all enrolled subjects who receive 1 or more doses of 
MLN0128. 
For purposes of defining the MTD and/or expansion phase recommended dose of 
MLN0128, subjects will be evaluated according to the starting dose level and planned 
schedule of MLN0128 during the first treatment cycle.  For most subjects, this will be the
cohort to which they were assigned.
2.2   
Full Analysis Set (FAS) Population
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of tumor response and other efficacy-related data. Subjects will be excluded from the FAS 
for the following reasons:

Failure to receive at least 1 dose of MLN0128

No post-baseline endpoint data subsequent to at least 1 dose of MLN0128

Lack of baseline data for those analyses that require baseline data
2.3   
Pharmacokinetics Population
The PK population consists of all subjects enrolled during the dose escalation phase of the 
study who receive at least one dose of MLN0128 or paclitaxel and have sufficient 
concentration-time data to calculate one or more PK parameters for either compound.
2.4   
Dose-Escalation Evaluable Population
Per the protocol subjects who receive ≥ 75% of the planned MLN0128 doses in Cycle 1 will 
be considered to have sufficient safety data/follow-up to support dose escalation. Subjects 
who withdraw from study before receiving at least 75% of the planned MLN0128 doses in 
the first cycle of treatment for reasons unrelated to study drug toxicity will be considered to 
have inadequate data to support dose escalation. In such cases, replacement subjects may be 
enrolled to receive the same starting dose of MLN0128 as the subjects who withdraw 
prematurely.


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
9
The dose-escalation evaluable population is defined as subjects who received 75% or more 
of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of 
planned doses because of study drug related AE (considered as a DLT).
The dose-escalation evaluable population will be used for the analysis of DLTs.
3.   
HYPOTHESES AND DECISION RULES
Not applicable in a phase 1 study.
4.   
INTERIM ANALYSIS
Not applicable.
5.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented that display the number of observations, 
mean, standard deviation (SD), median, minimum, and maximum for continuous variables, 
and the number and percent (of nonmissing) per category for categorical data, unless 
specified otherwise.  
Unless specified otherwise summary tables will be presented by schedule and MLN0128P
dose level [ordered] for the escalation phase and by arm (HER2- MLN0128P 8 mg QDx3d 
QW and HER2+ MLN0128P 8 mg QDx3d QW plus Trastuzumab) for the expansion cohort.
Study drug refers to MLN0128, Paclitaxel, or Trastuzumab.
5.1   
Sample Size Justification
Dose Escalation Phase 
Cohorts of 3 to 6 subjects will be enrolled in each MLN0128 dose cohort based on a 
standard phase 1 sequential dose escalation scheme. Each subject will participate in only 1 
dose cohort.  The total number of subjects to be enrolled in the dose escalation phase of the 
study is dependent upon the observed safety profile, which will determine the number of 
subjects per dose cohort, as well as the number of dose escalations required to achieve the 
MTD.


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
10
Expansion Phase
After the MTD of MLN0128 has been identified, 2 cohorts of subjects will be enrolled in
parallel:

Arm A will consist of approximately 12 to 15 safety-evaluable HER2– cancer 
subjects receiving MLN0128P

Arm B will consist of approximately 12 to 15 safety-evaluable HER2+ cancer 
subjects receiving MLN0128P plus weekly trastuzumab
Per Amendment number 6 the number of subjects was changed from 30 to 12-15.  
5.2   
Randomization and Stratification
Not applicable.
5.3   
Unblinding
Not applicable.
5.4   
Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations.  Data 
that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration.  
5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  
5.5   
Patient Disposition  
The number of subjects enrolled, in each analysis population, and the reasons each study 
drug was discontinued will be presented by schedule and MLN0128 dose level [ordered] for 


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
11
the escalation phase and by arm (HER2- and HER2+ plus Trastuzumab) for the expansion 
cohort.
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
The following demographic characteristics will be summarized for each cohort (escalation, 
expansion: HER2+, HER2- plus Trastuzumab separately) and all patients: age, sex, 
ethnicity, race, weight, and baseline ECOG performance status.
5.6.2   
Medical History
5.6.2.1  
General Medical History
Medical history findings will be in a by-patient listing.
5.6.2.2   Disease-Specific History
The following disease specific endpoints will be summarized for each cohort (escalation, 
expansion: HER2+, HER2- plus Trastuzumab separately) and all patients:

Years since initial diagnosis

Diagnosis at study entry
o
Breast cancer

ER and/or PR+/HER2-

ER and/or PR+/HER2+

ER-/PR-/ HER2+

ER-/PR-/ HER2-
[ HER2+ is defined as IHC 3 or FISH positive]
o
Lung cancer: Small Cell and NSCLC
o
Expansion only:  HER2 status (regardless of tumor type)

Stage of disease at initial diagnosis

Years since initial metastatic diagnosis of diagnosis of locally advanced inoperable 
cancer

Stage of disease at study entry
The number and percentage of subjects with prior surgery, prior radiation, and prior 
systemic anticancer therapies will be summarized for each cohort (escalation, expansion: 
HER2+, HER2- plus Trastuzumab separately) and all patients.  The following will be 
summarized for those subjects with prior systemic therapies:

Systemic regimen received (e.g. antibody therapy,  hormonal therapy)

Number of prior systemic treatment regimens

Setting of most recent systemic treatment

Best response to most recent systemic treatment


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
12

Reason most recent systemic treatment discontinued
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (March 2013 version). The number and percentage of patients taking 
concomitant medications will be tabulated by ATC classification and generic name in the 
ASaT population by schedule and MLN0128 dose level [ordered] for the escalation phase 
and by arm (HER2- and HER2+ plus Trastuzumab) for the expansion cohort.
5.7.2   
Study Treatments
All subjects will receive paclitaxel (80 mg/m2) on Days 1, 8, and 15 in combination with 
MLN0128 given either as QDx3d QW, QDx5d QW, or QW in each 4-week cycle. Once the 
MTD of MLN0128P is reached in the dose escalation phase, Her2+ cancer subjects enrolled 
into Arm B of the expansion phase will also receive trastuzumab weekly. 
5.7.2.1   Extent of Exposure
The overall duration of study drug administration (weeks: date of last dose – date of first 
dose + 1/ 7) and total number of cycles administered (distribution and summary statistics) 
will be summarized by schedule and MLN0128P dose level [ordered] for the escalation 
phase and by arm (HER2- and HER2+ plus Trastuzumab) for the expansion cohort.  The 
cumulative dose, dose per administration, and percentage of planned original dose for each 
drug (MLN0128, Paclitaxel, and Trastuzumab) will be summarized. The number and 
proportion of subjects with one or more dosage modifications will be tabulated along with 
the reason for dosage modification for each study drug.  For MLN0128 the number and 
proportion of subjects with intra-patient dose escalation will be summarized.
5.8   
Efficacy Analyses
The number and percent of patients in each response category, the objective response rate
(CR + PR), clinical benefit rate (CR + PR + SD), best response of SD <6 months, best 
response of SD ≥6 months will be presented by schedule and MLN0128P dose level 
[ordered] for the escalation phase and by arm (HER2- and HER2+ plus Trastuzumab) for 
the expansion cohort.  The objective response rate will be based on the subject’s best overall 
tumor response documented during the course of protocol therapy.  The duration of stable 


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
13
disease will be calculated relative to Study Day 1 for those subjects with a best response of 
stable disease and will be included in a data listing
RECIST Progression or Clinical Progression will be counted as progressive disease.
The duration of objective response will be calculated for subjects who achieve objective 
response and will be included in a data listing.  For such subjects, the duration of objective 
response is defined as the number of days from the start date of CR, or PR (whichever 
response is achieved first) to the first date that progressive disease is objectively 
documented.   Those subjects who did not progress are censored a the date of the last 
response assessment.
5.9   
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
5.9.1.1    PK Parameters for MLN0128
The following PK parameters will be estimated as data permit:
Parameter
Definition
Units
Cmax
Observed maximum concentration
ng/mL
Tmax
First time Cmax is observed
hr
AUC6hr
Area under the concentration-time curve, from time 0 to 
6 hr, estimated using the linear-log trapezoidal method
hr*ng/mL
AUC24hr
Area under the concentration-time curve, time 0 to 24 hr 
sample, estimated using the linear-log trapezoidal 
method
hr*ng/mL
lambdaz
Terminal disposition phase rate constant.  The presence 
of at least three points in the terminal phase, an r2 greater 
than 0.80, and a span equal to or greater than 1.5 are 
required to report lambdaz and the other PK parameters
that are calculating using lambdaz.
1/hr
t1/2
Terminal disposition phase half-life
hr
AUCinf
Area under the concentration-time curve, time 0 
extrapolated to infinity, estimated using the linear-log
trapezoidal method. 
hr*ng/mL
CL/F
Apparent clearance, extravascular dosing
L/hr
Vz/F
Apparent terminal phase volume of distribution, 
extravascular dosing
L
Rac6hr
Accumulation ratio based on AUC6hr
unitless


MLN0128
Statistical Analysis Plan, Study INK128-003
Confidential
14
5.9.1.2    PK Parameters: Paclitaxel
The following PK parameters will be estimated as data permit:
Parameter
Definition
Units
Cmax
Observed maximum concentration
ng/mL
Tmax
First time Cmax is observed
hr
AUC6hr
Area under the concentration-time curve, from time 0 to 
6 hr, estimated using the linear-log trapezoidal method
hr*ng/mL
AUC24hr
Area under the concentration-time curve, time 0 to 24 hr 
sample, estimated using the linear-log trapezoidal 
method
hr*ng/mL
lambdaz
Terminal disposition phase rate constant.  The presence 
of at least three points in the terminal phase, an r2 greater 
than 0.80, and a span equal to or greater than 1.5 are 
required to report lambdaz and the other PK parameters
that are calculating using lambdaz.
1/hr
t1/2
Terminal disposition phase half-life
hr
AUCinf
Area under the concentration-time curve, time 0 
extrapolated to infinity, estimated using the linear-log
trapezoidal method. 
hr*ng/mL
CL
Clearance
L/hr
Vss
Steady-state volume of distribution
L
5.9.1.3   Pharmacokinetic Analyses
All PK analyses will be performed using the pharmacokinetic population.
Pharmacokinetic Concentrations
Descriptive statistics (number of subjects, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, median, minimum, and maximum) will 
be used to summarize the plasma concentrations by compound, dosing schedule, dose level 
and scheduled time.  BQL values at the beginning of the profile will be set to zero. BQL 
values that occur after the first quantifiable point will be considered missing.
Linear and semi-logarithmic plots of the mean plasma concentration versus scheduled 
sampling time will be provided for each compound, dosing schedule, and dose level.  Linear 
and semi-logarithmic plots of individual plasma concentration versus actual sampling time 
will be provided for each compound, dosing schedule, and dose level. 
All individual subject plasma concentration data will be listed.


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MLN0128
Statistical Analysis Plan, Study INK128-003
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17

All TEAEs

TEAEs related to Study Drug

Grade 3 or greater TEAEs

Grade 3 or greater TEAEs related to Study Drug

Most common (at least 2 patients) TEAEs by maximum severity grade based on 
NCI-CTCAE (version 4.0)    [for each schedule in the escalation, and for each arm in 
the expansion cohort]
The number of patients with a DLT in Cycle 1 will be presented by schedule and 
MLN0128P dose level [ordered] for the escalation phase and by arm (HER2- and HER2+ 
plus Trastuzumab) for the expansion cohort (if experienced) based on the dose-escalation 
evaluable population. The dose-escalation evaluable population includes subjects from the 
ASaT population who receive at least 75% of the planned doses of MLN0128 in Cycle 1 or 
stop study drug before receiving 75% of the planned doses because of study drug related 
AE. Multiple concurrent adverse events leading to DLT will be considered a single DLT. 
Adverse events of interest will be tabulated for the following:
Adverse event of 
interest
MedDRA Preferred Term
Hyperglycemia
Glucose tolerance impaired, Hyperglycaemia, Impaired 
fasting glucose
Rash
Fixed eruption,  Mucocutaneous rash,  Rash,  Rash generalized,
Rash macular, Rash maculo-papular,  Rash maculovesicular, 
Rash morbilliform,  Rash rubelliform,  Rash scarlatiniform, 
Rash vesicular,  Dermatitis exfoliative,  Drug eruption,  Drug 
hypersensitivity,  Drug rash with eosinophilia and systemic 
symptoms, Reaction to drug excipients, Toxic skin eruption, 
Administration related reaction,  Erythema,  Generalised 
erythema,  Rash erythematous,  Rash popular,  Rash 
papulosquamous
Renal Insufficiency
(MedDRA 
Standardized Medical 
Query)
Acute phosphate nephropathy , Acute prerenal failure (Narrow), 
Anuria (Narrow), Azotaemia (Narrow), Continuous 
haemodiafiltration (Narrow), Dialysis (Narrow), Haemodialysis 
(Narrow), Neonatal anuria (Narrow), Nephropathy toxic 
(Narrow), Oliguria (Narrow), Peritoneal dialysis (Narrow), 
Prerenal failure (Narrow), Renal failure (Narrow), Renal failure 
acute (Narrow), Renal failure neonatal (Narrow), Renal 
impairment (Narrow), Renal impairment neonatal (Narrow), 
Albuminuria (Broad), Blood creatinine abnormal (Broad), 
Blood creatinine increased (Broad), Blood urea abnormal 
(Broad), Blood urea increased (Broad), Blood urea 
nitrogen/creatinine ratio, Creatinine renal clearance abnormal, 


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Statistical Analysis Plan, Study INK128-003
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Adverse event of 
interest
MedDRA Preferred Term
Creatinine renal clearance decreased, Creatinine urine abnormal 
(Broad), Creatinine urine decreased (Broad), Crystal 
nephropathy (Broad),  Glomerular filtration rate abnormal,  
Glomerular filtration rate decreased, Hypercreatininaemia 
(Broad), Nephritic syndrome (Broad),  Nephritis (Broad), 
Oedema due to renal disease (Broad), Protein urine present 
(Broad), Proteinuria (Broad), Renal function test abnormal 
(Broad), Renal transplant (Broad), Renal tubular disorder 
(Broad), Renal tubular necrosis (Broad), Tubulointerstitial 
nephritis (Broad), Urea renal clearance decreased (Broad), 
Urine output decreased (Broad)
Mucosal Inflammation
Burning sensation mucosal,  Mucosal erosion,  Mucosal 
excoriation,  Mucosal exfoliation,  Mucosal hyperaemia,  
Mucosal inflammation, Mucosal necrosis, Mucosal ulceration, 
Aphthous stomatitis, Mouth ulceration, Oral mucosa erosion, 
Stomatitis, Stomatitis haemorrhagic, Stomatitis necrotizing, 
Oral discomfort, Oral mucosal blistering, Oral mucosal 
erythema, Oral mucosal exfoliation, Oropharyngeal blistering, 
Oropharyngeal discomfort, Oropharyngeal pain
Asthenic Conditions
Asthenia, Fatigue, Lethargy, Listless, Malaise, Sluggishness, 
Muscle Weakness
5.10.1.2   Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious 
AE (SAE) will be summarized by MedDRA primary system organ class and preferred term:.

Serious TEAEs

Serious TEAEs related to Study Drug
In addition, a by-subject listing of the SAEs will be presented (the subject listing will 
contain all SAEs regardless of treatment emergent AE status).
5.10.1.3   Deaths
Fatal TEAEs that occur within 30 days of the last administration of study drug will be 
generated.   
5.10.1.4   Adverse Events Resulting in Study Drug Modifications
The following listings of TEAEs will be generated:


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
TEAEs resulting in discontinuation of study drug 

TEAEs resulting in modification or interruption of study drug
5.10.2   Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  Whenever available, laboratory values will be assigned 
toxicity grades using the NCI-CTCAE version 4.0.  These criteria may include qualifying 
definitions (e.g., clinical adverse event and/or requirement for concomitant medication) in 
addition to the specific laboratory value in the definition of the toxicity grades for some 
laboratory tests.  For such tests, the qualifying definitions will not be used for the 
assignment of toxicity grades. The number and proportion of subjects with shifts in CTCAE 
toxicity grades relative to the baseline toxicity grade will be summarized by schedule and 
MLN0128P dose level [ordered] for the escalation phase and by arm (HER2- and HER2+ 
plus Trastuzumab) for the expansion cohort.
For those laboratory tests not assigned NCI CTCAE toxicity grades the number and 
proportion of patients with shifts in laboratory values to outside the laboratory normal range 
relative to the baseline value will be summarized by schedule and MLN0128P dose level 
[ordered] for the escalation phase and by arm (HER2- and HER2+ plus Trastuzumab) for 
the expansion cohort.
5.10.3      Vital Signs
Vital sign results (diastolic and systolic blood pressure) and body weight will be 
summarized descriptively by schedule and MLN0128P dose level [ordered] for the 
escalation phase and by arm (HER2- and HER2+ plus Trastuzumab) for the expansion 
cohort as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to 
the baseline value.


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5.10.4   Electrocardiograms
Selected ECG parameters (ventricular rate, PR, QRS, QT, and QTc (Fridericia) ) will be 
summarized in the same manner as described for vital signs in Section 5.10.3.  All QT 
values will be converted to QTcF using Fridericia’s correction:
(sec)
[Note: convert RR recorded on ECG CRF from msec to sec, if the RR is not available use: 
60 seconds divided by the ventricular rate in beats/minute].
The change from baseline in QT/QTc interval and the number and percent of patients with 
increases >30 ms and >60 ms will be summarized.  Shifts from baseline to maximum post 
baseline QTcF values will be summarized based on the following categories:
≤ 450 ms, > 450-480 ms, > 480-500 ms and >500 ms.
5.10.5   ECOG Performance Status
ECOG performance status scores will be summarized in the same manner as described for 
vital signs in section 5.10.43 (maximum post-baseline only).
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol INK128-003 
Amendment 6 dated 25March 2013.  
The following analyses were planned in the protocol but not included in the statistical 
analyis plan:
1. Use of per-protocol population as a supportive analysis for tumo response is not 
relevant for a phase 1 study.
2. The 2- sided 95% exact binomial confidence interval around the estimate of the DLT 
rate.
3. Adverse incidence rates by cycle.
4. Descriptive statistics for laboratory values at each timepoint.


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7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Subject populations are defined in Section 2.
Baseline values are defined in Section 5.4.2.
Treatment-emergent AEs are defined in Section 5.10.1.1.
7.2.1
Study Drug
The term “study drug” represents MLN0128, Paclitaxel or Trastuzamab.
7.2.2
Study Day 1
Study Day 1 corresponds to the date of the first dose of study drug. For subjects who
receive 1 or more doses of study drug, the start date recorded on the Study Drug 
Administration (Cycle 1 – Day 1) CRF will be used to determine Study Day 1.
7.2.3
Study Day
Study Day represents the elapsed number of days from Study Day 1, inclusive.
Study Day n = (Date of assessment – Date of Study Day 1) + 1 day
Unless otherwise specified, the timing of all study-related events, assessments, and 
interventions will be calculated relative to Study Day 1.  Study Day −1 will be the day 
before Study Day 1, and in general, negative days will be measured backwards starting from 
Study Day −1.
7.2.4
Cycle 1 Day 1
The first 28-day treatment cycle will begin with the first dose of study drug, and will be 
denoted as “Cycle 1 Day 1”.  In general, the start date of each cycle (i.e., Day 1 of Cycle k, 
where k=1 to maximum number of cycles started) equals the date of the first dose of study 
drug administered in the corresponding cycle.  If study drug is permanently discontinued, 


MLN0128
Statistical Analysis Plan, Study INK128-003
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then the cycle and cycle day for study-related assessments done after the last cycle will be 
replaced in the tables, figures, and listings with the visit name (eg, Termination Visit).  The 
visit date and study day also will be used to identify the timing of such assessments.
7.2.5
Cycle k Day j
Day j represents the elapsed number of days since the first dose of protocol therapy in 
Cycle k.
Day j = (Date of assessment – Date of Day 1 in Cycle k) + 1
Unless otherwise specified, the timing of study-related visits and assessments will be 
calculated relative to Day 1 in each cycle.
As noted previously, if study drug is permanently discontinued, then the cycle and cycle day 
for study-related assessments done after the last cycle of study drug will be replaced in the 
tables, figures, and listings with the visit name (eg, Termination Visit).  The visit date and 
study day also will be used to identify the timing of such assessments. 
7.2.6
Age at Screening
Age will be calculated in years relative to the date the informed consent is signed based on 
the following SAS programming statement:
Age = floor ((intck (‘month’, birthdt, icdt) – (day (icdt) < day (birthdt))) / 12);
For patients whose day and month of birth may not be available due to confidentiality 
agreements, age (and any other variables where this information is needed) will be 
calculated assuming a birth day and month of July 1st.
8.   
REFERENCES
Not applicable.