MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma

OUTLINE: This is a multi-center trial.

The phase 1 dose escalation trial will evaluate MLN0128 in a standard 3+3 successive cohort
design to identify the highest planned dose level. Phase II trial subjects will be 1:1
randomized to receive either MLN0128 (investigational arm) or sorafenib (control arm).

PHASE I DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 (dose level +1) will consist of 3-6 evaluable patients who will receive MLN0128 15mg
on day 1 of the 28-day cycle.

Cohort 2 (dose level +2) will consist of 3-6 evaluable patients who will receive MLN0128 20mg
on day 1 of the 28-day cycle.

Cohort 3 (dose level +3) will consist of 3-6 evaluable patients who will receive MLN0128 30mg
on day 1 of the 28-day cycle.

Subjects will be evaluated for dose limiting toxicity (DLT) in the first 28 days of treatment
(1 cycle). However, decisions to move to next dose escalation cohort will not be made until
all subjects complete 2 cycles of therapy at a given dose. There will be no further dose
escalation beyond dose level +3.

PHASE II INVESTIGATIONAL TREATMENT:

Randomization will take place following completion of the screening evaluations and
eligibility assessments. Stratification factors will be employed during randomization to
minimize between-arm assignment imbalance.

- 1 Child-Pugh score 5-6

- 2 Child-Pugh score 7

Within the strata, subjects will be randomly assigned with equal probability to either the
investigational arm (Arm A: MLN0128) or the control arm (Arm B: sorafenib).

Arm A: MLN0128 will be administered orally at the recommended phase II dose (RP2D) once
weekly.

Arm B: Sorafenib will be administered at 400mg PO BID daily, with dose adjustment per
standard of care.

A new treatment cycle (1 cycle = 28 days) will only be initiated when all of the following
conditions are met:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L

- Platelets ≥ 50 x 10*9/L

- Non-hematologic treatment related toxicities have improved to grade 1 or resolved per
Common Terminology Criteria for Adverse Events v4.0 (CTCAE)

Treatment may continue until progression, unacceptable toxicity, or withdrawal from study.

Estimated Life Expectancy: ≥ 3 months

Subjects must have adequate organ function, as specified below, within 7 days before study
registration:

Bone marrow reserve consistent with:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L

- Platelet count ≥ 50 x 10*9/L

- Hemoglobin ≥ 9 g/dL

Hepatic:

- Total bilirubin ≤ 2 x upper limit of normal (ULN)

- Transaminases (aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase
(SGOT) and alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤
5 x ULN

Renal:

- Creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or based on
urine collection (12 or 24 hour)

Metabolic:

- Fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL.

- Glycosylated hemoglobin (HbA1c) <7.0%

Inclusion Criteria:

- Male or female subjects 18 years or older at the time of informed consent.

- Voluntary written consent must be signed before performance of any study related
procedure not part of standard medical care, with the understanding that the subject
may withdraw consent at any time without prejudice to future medical care.

- Females of childbearing potential must agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent through
90 days after the last dose of study drug, or agree to completely abstain from
heterosexual intercourse.

- Females of childbearing potential must have a negative serum pregnancy test within 7
days prior to prior to registration for protocol therapy. NOTE: Female subjects are
considered of childbearing potential unless they are surgically sterile (they have
undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they
are naturally postmenopausal for at least 12 consecutive months.

- Male subjects, even if surgically sterilized (i.e., status post-vasectomy), must agree
to practice effective barrier contraception during the entire study treatment period
and through 120 days after the last dose of study drug, or agree to completely abstain
from heterosexual intercourse.

- Subjects must have a diagnosis of measurable advanced or metastatic hepatocellular
carcinoma (HCC). Advanced HCC is defined as disease not amenable to surgery, ablation,
transplant, or embolic therapy.

- Phase II subjects must be willing to provide a tissue biopsy prior to registration if
archived HCC tumor tissue is not available for correlative studies.

- For the phase I cohort, subjects with one prior systemic treatment are eligible.

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

- Adequate organ function, as specified below, within 28 days before study registration:

- Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L;
platelet count ≥ 50 x 10^9/L; hemoglobin ≥ 9 g/dL;

- Hepatic: total bilirubin ≤ 2 x upper limit of normal (ULN), transaminases (aspartate
aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine
aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 5 x ULN

- Renal: creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or
based on urine collection (12 or 24 hour);

- Metabolic: Glycosylated hemoglobin (HbA1c) ≤7.0%, fasting serum glucose (≤ 130 mg/dL)
and fasting triglycerides ≤ 300 mg/dL.

- Ability to swallow oral medications.

- Measurable disease according to RECIST v1.1 and obtained by imaging within 28 days
prior to registration for protocol therapy.

- Subjects who have a history of brain metastasis are eligible for the study provided
all the following criteria are met:

- Must have completed their treatment for brain metastasis

- Must be asymptomatic

- Must not have evidence of disease progression for ≥3 months or hemorrhage after
treatment;

- Must be off-treatment from dexamethasone for 4 weeks prior to study registration
and

- Must not have an ongoing requirement for dexamethasone or anti-epileptic drugs.

- Prior locoregional liver directed therapy is allowed as long as treatment was at least
6 weeks prior to study registration, and clear progression is demonstrated by RECIST
v1.1 criteria. Subject must have recovered from the acute toxic effects (≤ grade 1
CTCAE v4) of previous anti-cancer treatment prior to study enrollment; the only
exception is that grade 2 neuropathy is permitted.

- Prior radiation therapy is allowed to < 25% of the bone marrow, but is not permitted
within 28 days prior to study registration.

- Estimated life expectancy > 3 months as determined by the treating physician.

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria are not to be enrolled in the
study:

- Female subjects who are both lactating and breastfeeding

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.

- Treatment with any investigational products within 28 days prior to study
registration.

- No prior systemic treatment is allowed, except for subjects in the phase I cohort who
are permitted one prior systemic treatment.

- Failed to recover from the reversible effects of prior anticancer therapies with the
exception of alopecia and grade 2 neuropathy.

- Have initiated treatment with bisphosphonates less than 30 days prior to study
registration. Concurrent bisphosphonate use is only allowed if the bisphosphonate was
initiated at least 30 days prior to study registration.

- Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI
disease, or for an unknown reason that may alter the absorption of MLN0128.

- No condition that could affect the absorption of study drug, including any of the
following:

- Malabsorption syndrome

- Disease significantly affecting gastrointestinal function

- Bowel obstruction or sub-obstruction

- History of any of the following within the last 6 months prior to study registration:

- Ischemic myocardial event, including angina requiring therapy and artery
revascularization procedures

- Ischemic cerebrovascular event, including transient ischemic attack (TIA) and
artery revascularization procedures

- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular
fibrillation or ventricular tachycardia)

- Placement of a pacemaker for control of rhythm

- New York Heart Association (NYHA) Class III or IV heart failure

- Pulmonary embolism

- Significant active cardiovascular or pulmonary disease at the time of study
registration, including:

- Uncontrolled high blood pressure (i.e., systolic blood pressure >160 mm Hg,
diastolic blood pressure > 95 mm Hg)

- Pulmonary hypertension

- Uncontrolled asthma or O2 saturation < 90% by ABG (Arterial Blood Gas) analysis
or pulse oximetry on room air

- Significant valvular disease; severe regurgitation or stenosis by imaging
independent of symptom control with medical intervention, or history of valve
replacement

- Medically significant (symptomatic) bradycardia

- History of arrhythmia requiring an implantable cardiac defibrillator

- Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated
demonstration of QTc interval > 480 milliseconds, or history of congenital long
QT syndrome, or torsades de pointes)

- Initiation of treatment with hematopoietic growth factors, transfusions of blood and
blood products, or systemic corticosteroids (either IV or oral steroids, excluding
inhalers) within 1 week prior to study registration (subjects already receiving
erythropoietin on a chronic basis for ≥ 28 days are eligible).

- Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
active central nervous system disease, active infection, or any other condition that
could compromise participation of the subject in the study.

- Cirrhosis with Child-Pugh score > 7

- Variceal bleeding within 1 month prior to study registration.

- Refractory encephalopathy or ascites

- Known HIV positivity

- Hepatitis B surface antigen (HBsAg) positivity without active treatment. A subject
found to be HBsAg positive should be on antiviral therapy for at least two weeks prior
to study registration.

- Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19
or CYP2C19 within 7 days prior to study registration.

- Subjects requiring daily or chronic use of a proton pump inhibitor (PPI) and/or having
taken a PPI within 7 days prior to study registration.