Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma

PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerable dose of sapanisertib (MLN0128 [TAK-228])
within this patient population. (Phase I) II. To determine the differences in
progression-free survival (PFS) in patients with sarcoma who receive MLN0128 (TAK-228) as
compared to pazopanib (pazopanib hydrochloride). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate adverse events. (Phase I/II) II. To evaluate overall response rate (ORR),
clinical benefit rate (CBR), and duration of response (DOR). (Phase I/II) III. To evaluate
time to progression (TTP) and overall survival (OS). (Phase I/II)

EXPLORATORY OBJECTIVES:

I. To evaluate PFS and secondary endpoints within patients crossing over to MLN0128
(TAK-228), upon disease progression during treatment with pazopanib. (Phase II) II. To
evaluate the 4 month CBR observed within patients treated with MLN0128 (TAK-228) and grouped
by histologically defined cohorts. (Phase II)

OUTLINE: This is a phase I, dose-escalation study, followed by a randomized phase II study.

PHASE I: Patients receive sapanisertib orally (PO) on days 1, 8, 15, and 22 in the absence of
disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sapanisertib as in Phase I. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pazopanib hydrochloride PO once daily (QD) on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients
experiencing disease progression may crossover to Arm I.

After completion of study treatment, patients are followed up at 4 weeks and then every 6
months for 2 years.

Inclusion Criteria:

- Patients must have slides available for submission to central pathology review; this
review is mandatory prior to registration to confirm eligibility and proper cohort
assignment

- HISTOLOGIC COHORT 1: Undifferentiated pleomorphic sarcoma (includes: malignant
fibrous histiocytoma, myxofibrosarcoma, high grade sarcoma not otherwise
specified [NOS])

- HISTOLOGIC COHORT 2: Leiomyosarcoma (either uterine or extra-uterine)

- HISTOLOGIC COHORT 3: Other (either malignant peripheral nerve sheath tumor or
synovial sarcoma); during the phase II portion of the study, enrollment will be
limited to maximum of 25 patients in this cohort

- Note that the phase I is limited to the histologic subtypes listed above;
since patients will be enrolling onto dose cohorts during the phase I, they
will not enroll onto specific histologic cohorts, although the histologic
subtype informed will be collected during patient enrollment

- Histologic documentation: Eligible patients must have histopathologically confirmed
sarcoma of one of the subtypes listed, by central review

- Locally advanced or metastatic disease; locally advanced disease is defined as disease
not amenable to local therapy such as surgery and/or radiation

- Measurable disease

- Progression on at least one prior systemic chemotherapy for advanced, unresectable or
metastatic disease; prior adjuvant or neoadjuvant therapy is not included as prior
systemic chemotherapy unless treatment occurred within the 6 months prior to study
enrollment

- There is no limit to the number of prior lines of treatment a patient has received

- No treatment with biological therapy, immunotherapy, chemotherapy, investigational
agent for malignancy, or radiation =< 28 days before study registration; no treatment
with nitrosourea or mitomycin =< 42 days before study registration

- No treatment with radiation therapy =< 28 days before study registration

- Patients should have resolution of any toxic effects of prior therapy (except
alopecia) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE), version 4.0, grade 1 or less

- Prior treatment with pazopanib or any phosphoinositide 3-kinase (PI3K), mTOR, protein
kinase B (AKT), or dual PI3K/mTOR complex (CREB regulated transcription coactivator
[TORC]1/TORC2) inhibitors will be prohibited

- Not pregnant and not nursing; for women of childbearing potential only, a negative
pregnancy test done =< 7 days prior to registration is required

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Patient history: patients who have any of the following are NOT eligible:

- Central nervous system (CNS): Symptomatic, untreated, or uncontrolled brain
metastases present

- Heme: Active bleeding or bleeding diathesis

- Gastrointestinal (GI):

- Abdominal fistula, GI perforation, or intra-abdominal abscess within 28 days
prior to registration

- Acute GI bleed within 28 days of registration

- Diabetes mellitus: Patients with diabetes mellitus with inadequate control, based
on either a glycosylated hemoglobin (Hgb A1c) of > 7.0 or fasting blood glucose
above or equal to 130 mg/dL

- Cardiac and vascular disorders:

- History of congenital long QT syndrome or torsades de pointes

- Any arrhythmia that is currently not rate-controlled (rate between 60 and
100)

- Prolongation of corrected QT interval via Fridericia's formula (QTcF) > 480
msec

- Ongoing unstable angina

- Symptomatic peripheral vascular disease

- Arterial thrombosis within 28 days of registration including transient
ischemic attack (TIA), cerebrovascular accident (CVA), myocardial infarction
(MI)

- Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) must be
on a stable dose of anticoagulation for 14 days prior to registration

- Uncontrolled hypertension, defined as blood pressure (BP) > 140/90

- Multi gated acquisition scan (MUGA) with ejection fraction (EF), 50% or
echocardiogram (echo) with low EF

- Class III or IV congestive heart failure (CHF) within 28 days of
registration

- Chronic concomitant treatment with proton pump inhibitors must discontinue the drug
for 7 days prior to registration on the study

- Chronic concomitant treatment with strong inhibitors of cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inhibitors must discontinue the drug for 14 days
prior to registration on the study

- Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients
must discontinue the drug 14 days prior to the start of study treatment

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Creatinine =< 1.5 x upper limit of normal (ULN)

- Total bilirubin =< 1.5 x upper limit of normal (ULN); unless patient has Gilbert
disease

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x upper limit of
normal (ULN); if liver metastases, =< 5 x upper limit of normal (ULN)

- Urine protein creatinine (UPC) =< 1; if UPC >= 1, then a 24-hour urine protein must be
assessed; eligible patients must have a 24-hour urine protein value < 1 g/L

- Thyroid stimulating hormone (TSH) within normal limits (WNL); supplementation is
acceptable to achieve a TSH WNL; in patients with abnormal TSH however if the Free T4
is normal and patient is clinically euthyroid, patient is eligible