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

This phase I/II trial studies the side effects and best dose of sapanisertib and to see how well it works compared to pazopanib hydrochloride in treating patients with sarcoma that is too large to be removed (locally advanced) or has spread to other areas of the body (metastatic). Sapanisertib and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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. Cycles 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. Cycles 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.

Eligibility Criteria:
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; because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown and an agent that has known genotoxic, mutagenic and teratogenic effects; therefore, 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 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