TORC1/2 Inhibitor MLN0128 and Bevacizumab in Treating Patients With Recurrent Glioblastoma or Advanced Solid Tumors

This phase I trial studies the side effects and best dose of raptor/rictor-mammalian target of rapamycin (mTOR) (TORC1/2) inhibitor MLN0128 when given in combination with bevacizumab in treating patients with glioblastoma, a type of brain tumor, or a solid tumor that has spread and not responded to standard treatment. TORC1/2 inhibitor MLN0128 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the progression of tumors by blocking the growth of new blood vessels necessary for tumor growth.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose and recommended phase 2 dose (MTD/RP2D) of daily oral MLN0128 (TORC1/2 inhibitor INK128) when administered with bevacizumab in patients with advanced solid tumors including recurrent glioblastoma (GBM).

II. To evaluate the overall safety and tolerability of the combination of MLN0128 and bevacizumab.

SECONDARY OBJECTIVES:

I. To assess the preliminary anti-tumor activity of the combination of MLN0128 and bevacizumab, as determined by response rate (RR), progression-free survival (PFS) and overall survival (OS).

II. To assess tolerability throughout study therapy with MLN0128 and bevacizumab, including beyond the MTD interval with the following measures of cumulative treatment-related toxicities: frequency of toxicities leading to missed doses or delays; percentage of cycles given or not within 7 days of their scheduled times; percentage of actual planned dosage administration; percentage of patients that discontinue study drugs due to treatment related toxicity.

TERTIARY OBJECTIVES:

I. To assess cerebrospinal fluid (CSF) penetration of MLN0128 in combination with bevacizumab in patients with recurrent GBM by evaluating the plasma and CSF concentrations of MLN0128 in the absence and presence of bevacizumab.

II. To perform archival tumor analysis for markers of dysregulated cell signaling that may predict response to mechanistic target of rapamycin (mTOR) inhibitor therapy such as epidermal growth factor receptor (EGFR) (expression by immunohistochemistry \[IHC\] and amplification by fluorescent in situ hybridization \[FISH\]), phosphatase and tensin homolog (PTEN) (expression by IHC and deletion by FISH), phosphorylated (p)-protein kinase B (AKT), p-ribosomal protein S6 kinase (S6K), p-eukaryotic translation initiation factor 4E binding protein 1 (4EBP), p-mTOR and p-mitogen-activated protein kinase 1 (Erk) in patients with recurrent GBM.

III. To analyze select phosphorylated proteins (ERK, AKT, mTOR, 4EBP1, glycogen synthase kinase 3-beta \[GSK3beta\], ribosomal protein S6 kinase, 70kDa, polypeptide 2 \[p70S6K\], rS6) from tumor biopsies obtained at baseline and after treatment with MLN0128 from endometrial and ovarian cancer patients enrolled in stage 2.

IV. To analyze circulating plasma levels of angiogenic growth factors before, during and after treatment with MLN0128 and bevacizumab V. To perform genetic mutation analysis and proteomic analysis of tissue from biopsies of endometrial and ovarian cancer patients including analysis of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1) and PTEN.

OUTLINE: This is a dose-escalation study of MLN0128.

Patients receive TORC1/2 inhibitor MLN0128 orally (PO) once daily (QD) and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then annually thereafter.

Eligibility Criteria:
Inclusion Criteria:

* Patients must have a histologically/cytologically confirmed diagnosis of recurrent glioblastoma or an advanced solid tumor in which bevacizumab has shown benefit in specific disease population and for which standard or curative measures do not exist or are no longer effective
* Measurable or evaluable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for non-GBM tumors and by Response Assessment in Neuro-Oncology (RANO) criteria for GBM
* For stage 1 (all patients) and dose expansion (stage 2) endometrial and ovarian cancer cohorts, participants are allowed following unlimited prior therapy; for stage 2 GBM participants, no more than 2 prior relapses are allowed; for these patients, relapse is defined as progression following initial therapy (i.e. radiation +/- chemo if that was used as initial therapy) or a subsequent therapy; the intent therefore is that GBM patients enrolling onto stage 2 had no more than 3 prior therapies (initial and treatment for 2 relapses); if the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute 1 relapse

  * NOTE: for participants who had prior therapy for a low-grade glioma, the surgical diagnosis of glioblastoma will be considered the first relapse; therefore, these participants may have had more than 3 prior therapies
* Patients must have recovered from clinically significant toxicity of prior therapy to grade =\< 1 or pre-treatment baseline; the following intervals from previous treatments are required prior to day 1 of study therapy:

  * 12 weeks from the completion of radiation for recurrent GBM unless there is surgical diagnosis of recurrence or a new lesion that was not previously radiated
  * 6 weeks from a nitrosourea chemotherapy
  * 3 weeks from a non-nitrosourea chemotherapy
  * 4 weeks from an investigational agent (not Food and Drug Administration \[FDA\] approved) (or 5 half lives, whichever is shorter)
  * 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.) (or 5 half lives, whichever is shorter)
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Absolute neutrophil count \>= 1,500/uL
* Platelets \>= 100,000/uL
* Hemoglobin \>= 9.0 g/dL
* Total bilirubin \< 1.5 x institutional upper limit of normal with direct bilirubin within normal limits except for participants with Gilbert's disease
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal (=\< 5 x upper limit of normal \[ULN\] if liver metastases are present)
* Creatinine \< 1.5 x normal institutional limits OR creatinine clearance \>= 50 mL/min/1.73 m\^2 for patients with creatinine level above institutional normal based either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour)
* Metabolic: fasting serum glucose (=\< 130 mg/dL) and fasting triglycerides =\< 300 mg/dL
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 6 months after completion of MLN 0128 or bevacizumab administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of MLN0128 or bevacizumab administration
* Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for \>= three years prior to registration
* Solid tumor patients must be off corticosteroids prior to registration; if GBM patient is receiving corticosteroids, patient must be on a stable or decreasing dose of corticosteroids for at least 5 days prior to baseline magnetic resonance imaging (MRI) or computed tomography (CT); if steroids are added or the steroids dose is increased between the date of the screening MRI or CT and the start of treatment, a new baseline MRI or CT is required
* Patients must be able to swallow whole capsules
* Ability to understand and the willingness to sign a written informed consent document
* For stage 2 GBM participants, a block of paraffin embedded tissue or 30 unstained slides at standard 4-5 um thickness from any prior surgery demonstrating GBM pathology must be available for submission
* Stage 2 endometrial and ovarian cancer patients must have at least one lesion amenable to biopsy; this determination will be made by a member of the interventional radiology team or surgical associate investigator and an associate investigator; this requirement is not necessary for patients in stage 1
* Solid tumor patients in stage 2 must have a diagnosis of papillary serous, endometrioid or clear cell endometrial carcinoma or, high grade serous, clear cell, endometrioid or mucinous ovarian, fallopian or primary peritoneal carcinoma

Exclusion Criteria:

* Concurrent administration of any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 or bevacizumab
* For all stage 2 participants, no prior treatment with mTOR, PI3 kinase or Akt inhibitors; prior treatment with mTOR, PI3 kinase or Akt inhibitors allowed in stage 1 only
* For stage 2 GBM participants, no prior treatment with bevacizumab/vascular endothelial growth factor receptor (VEGFR) inhibitors; prior treatment with bevacizumab/VEGFR inhibitors is allowed in stage 1 for all participants, as well as stage 2 endometrial and ovarian cancer participants
* Stage 1 solid tumor and stage 2 endometrial and ovarian cancer participants with known central nervous system (CNS) metastatic lesions which are symptomatic and/or growing; patients previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll; brain metastasis must be stable for 1 month with verification by imaging (brain MRI completed at screening demonstrating no current evidence of progressive brain metastases); CNS imaging will not be mandated for asymptomatic patients with no history of CNS metastases
* Concurrent use of enzyme-inducing anti-epileptic drugs (EIAED); patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs; patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of MLN0128
* Subjects taking strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) and cytochrome P450, family 2, subfamily C, polypeptide 19 (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 subject requires treatment with 1 or more of the strong CYP3A4 and CYP2C19 inhibitors and/or inducers, the principal investigator should be consulted
* Concurrent use of herbal supplements and other non-traditional medications; all herbal supplements and other non-traditional medications must be stopped before time of registration
* Concurrent use of anti-coagulants (warfarin, etc.) other than low-molecular weight heparin (LMWH); medication must be stopped before time of registration; if patient has recently been on anti-coagulants other than LMWH, patient must have international normalized ratio (INR) =\< 2
* Evidence of any significant intracranial hemorrhage, as determined by the treating investigator, within 6 weeks from registration or as seen on most recent MRI prior to screening/baseline MRI
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
* History of any of the following within 6 months prior to start of MLN0128:
* Left ventricular ejection fraction (LVEF) =\< 55% as determined by multi gated acquisition (MUGA) scan or echocardiogram (ECHO)
* Heart failure \>= New York Heart Association (NYHA) grade 3
* Significant ST depression of \>= 1.5 mm in 2 or more leads and/or T wave inversions in \>= 2 leads
* Complete left bundle branch block
* Right bundle branch block + left anterior hemiblock (bi-fascicular block)
* Congenital long QT syndrome
* QT interval corrected by Fridericia's formula (QTcF) \> 450 msec on screening electrocardiogram (ECG)
* Requirement of inotropic support (excluding digoxin)
* History or presence of clinically significant ventricular or atrial tachyarrhythmias, or cardiac arrest
* Clinically significant resting bradycardia
* Presence of unstable atrial fibrillation (ventricular response \> 100 beats per minute)
* Patients with stable atrial fibrillation are allowed in the study provided they do not meet the other cardiac exclusion criteria
* History of arrhythmia requiring an implantable cardiac defibrillator
* Angina pectoris =\< 12 months prior to starting drug
* Acute myocardial infarction =\< 12 months prior to starting drug
* Any valve disease Common Terminology Criteria for Adverse Events (CTCAE) grade
* Ischemic myocardial event including angina requiring therapy and artery revascularization procedures
* Placement of a pacemaker for control of rhythm
* Pulmonary embolism
* Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral MLN0128 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection that requires nutritional support)
* Use of hematopoietic colony-stimulating growth factors (e.g. filgrastim \[G-CSF\], sargramostim \[GMCSF\], lanimostim \[M-CSF\]) =\< 2 weeks prior to starting study drug; erythropoietin, darbepoetin and erythropoietin-biosimilars are allowed for as long as they have been initiated at least 2 weeks prior to study enrollment
* Pregnant or nursing women; breastfeeding should be discontinued if the mother is treated with MLN0128
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; if an HIV-positive patient has adequate cluster of differentiation (CD4) counts (CD4 above the lower limit of institutional normal) and is on antiretroviral therapy with newer agents, which are not strong cytochrome (CYP) inhibitors, they will be eligible
* Uncontrolled high blood pressure (i.e., systolic blood pressure \>= 160 mmHg, diastolic blood pressure \>= 90 mmHg)
* Pulmonary hypertension
* Uncontrolled asthma or oxygen (O2) saturation \< 90% by ABG (arterial blood gas) analysis or pulse oximetry on room air
* Participants with poorly controlled diabetes mellitus (defined as hemoglobin A1c \[HbA1c\] \> 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
* Urine protein should be screened by urinalysis; if protein is 2+ or higher, 24 hour urine protein should be obtained and the level should be \< 1000 mg for patient enrollment
* Serious or non-healing wound, ulcer or bone fracture
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1
* Invasive procedures defined as follows:

  * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to day 1 therapy
  * Anticipation of need for major surgical procedures during the course of the study
  * Core biopsy within 7 days prior to day 1 therapy
* Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
* Evidence of bleeding diathesis or coagulopathy
* Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies