Oral ONC201 in Treating Patients With Advanced Solid Tumors

Inclusion Criteria:

* Patients with an advanced solid tumor that is refractory to standard treatment, or for which no standard therapy is available, or the subject refuses standard therapy
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 1
* All patients must have measurable or evaluable disease defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria; if the patient has received prior radiation therapy one measurable lesion must be outside the irradiated field; lesions within an irradiated field will be followed as non-target lesions and considered evaluable; if the only site of measurable disease is within a previously irradiated field then 6 months must have elapsed between the completion of radiation therapy and entry on study to be considered measurable
* Patients are eligible for enrollment if they have not had prior investigational or approved cytotoxic chemotherapy within 28 days prior to the first dose (week 1, day 1); 42 days in the case of alkylating agents; 28 days or 5 half-lives (whichever is less; but not less than 14 days) in case of investigational or approved molecularly targeted agent; 14 days in the case of radiotherapy; any number of prior therapies is allowable
* All adverse events grade =\< 2 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be resolved, except for alopecia or neuropathy; patients are eligible for enrollment if they have had no surgery in the prior 6 weeks (minor surgical procedures such as skin biopsies and port placement done on an outpatient basis do not require a waiting period)
* Absolute neutrophil count \>= 1,500/mcL
* Platelets \>= 100,000/mcL
* Hemoglobin \>= 9.0 mg/dL without transfusion in 2 prior weeks
* Total bilirubin within normal range; for patients with liver metastases, serum bilirubin =\< 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate transaminase \[SGPT\]) =\< 2.5 x upper limit of normal
* Measured OR estimated creatinine clearance \>= 40 mL/min/1.73 m\^2 for patients with creatinine levels above normal
* Men or women treated or enrolled on this protocol must agree to use double barrier contraceptives; oral, implantable, or injectable contraceptives are not considered effective for this study; women of child-bearing potential must have a negative serum pregnancy test =\< 72 hours prior to initiating treatment; subjects must agree to use double barrier contraceptive therapy for the duration of study participation, and 4 months after completion of ONC201 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
* Tumor specimen (paraffin-embedded block or frozen tissue) from prior resection or biopsy available that is sufficient to perform pharmacodynamic assays (\>= 3 slides for immunohistochemistry \[IHC\]) - mandatory for patients in the dose expansion cohort only
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Patients with symptomatic brain metastases are excluded; however, patients with asymptomatic central nervous system (CNS) metastases may participate in this trial; the patient must have completed any prior local treatment for CNS metastases \> 28 days prior to study entry including radiotherapy or surgery; patients receiving steroids for CNS metastases may not participate on this study
* Prior bevacizumab for treatment of glioblastoma or high grade glioma
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
* Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator
* Patients with a known human immunodeficiency virus (HIV)-positive test on combination antiretroviral therapy are ineligible for the initial first-in-man trial
* Patient has active cardiac disease including any of the following:

  * Corrected QT (QTc) \> 500 msec on screening electrocardiogram (ECG) (using the QTc Fridericia \[F\] formula)
  * Angina pectoris that requires the use of anti-anginal medication
  * Ventricular arrhythmias except for benign premature ventricular contractions
  * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
  * Conduction abnormality requiring a pacemaker
  * Valvular disease with document compromise in cardiac function
  * Symptomatic pericarditis
* Patient has a history of cardiac dysfunction including any of the following:

  * Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function
  * History of documented congestive heart failure (New York Heart Association functional classification III-IV)
  * Documented cardiomyopathy
* Patient with stroke in the last 3 months
* Patients with a history of seizures with in the past 3 months
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ONC201 (uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
* Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM-CSF\]) =\< 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
* Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives are not considered effective for this study
* Women of child-bearing potential must have a negative serum pregnancy test =\< 72 hours prior to initiating treatment
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment and for 16 additional weeks after stopping treatment; the highly effective contraception is defined as either:

  * True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  * Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient
  * Use of a combination of any two of the following (a+b):

    1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    2. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
  * Oral contraception, injected or implanted hormonal methods are not allowed
  * Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during treatment and for an additional 16 weeks after stopping treatment
  * Female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy