Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery

• Pathologically confirmed diagnosis of intermediate or high-grade soft tissue sarcoma for which single-agent doxorubicin is appropriate therapy, including but not limited to:

  • Synovial sarcoma
  • Fibrosarcoma
  • Undifferentiated sarcoma
  • Liposarcoma
  • Leiomyosarcoma
  • Angiosarcoma
  • Malignant peripheral nerve sheath tumor
  • Pleomorphic rhabdomyosarcoma
  • Myxofibrosarcoma
  • Epithelioid sarcoma
  • Undifferentiated pleomorphic sarcoma
• Locally advanced unresectable or metastatic disease with no standard curative therapy available
• Archival tumor tissue retinoblastoma-associated protein (pRb) positive by immunohistochemistry (IHC)
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• All races and ethnic groups will be included; for subjects between the ages of 12-18 years only, body surface area (BSA) must be >= 1.28 m\^2
• Ejection fraction of >= 50% by echocardiogram or multi-gated acquisition (MUGA) scan
• Female subjects of childbearing potential must have a negative urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at time of screening and within 14 days prior to planned first dose of ribociclib
• Willing to use adequate contraception throughout the study and for 3 weeks after study drug discontinuation

• Meets the following standard 12-lead electrocardiography (ECG) parameters at screening (defined as the mean of the triplicate ECGs; ECGs done in triplicate do not have a defined interval between assessments):

  • Corrected QT using Fridericia's correction formula (QTcF) interval at screening \< 450 msec for males and \< 470 msec for females (using Fridericia's correction)
  • Resting heart rate =\< 100 beats per minute (bpm)
• Absolute neutrophil count (ANC) >= 1.5 K/cu mm
• Platelets (no transfusion within prior 7 days) >= 100 K/cu mm
• Hemoglobin (no transfusion within prior 7 days) >= 9.0 g/dL
• Total bilirubin \< institutional upper limit of normal (ULN), except for subjects with documented Gilbert's syndrome, for which =\< 3.0 x ULN or direct bilirubin =\< 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT) in the absence of liver metastases: =\< 2.5 x ULN; if the subject has liver metastases: \< 5 x ULN
• Serum creatinine \< 1.7 mg/dL
• Potassium within institutional normal limit (WNL)
• Corrected calcium WNL
• Magnesium WNL

• International normalized ratio (INR) =\< 1.5

  • Use of rivaroxaban, apixaban, edoxaban or warfarin is an exclusion criteria; therapy with heparin, low molecular weight heparin (LMWH), dabigatran or fondaparinux is allowed
• All prior treatment-related toxicities resolved to =\< grade 1 or are determined to be clinically stable by the investigator

• Has completed prior therapies according to the criteria below:

  • Cytotoxic chemotherapy - at least 21 days since last dose prior to first dose of ribociclib
  • Small molecule inhibitors - at least 14 days since last dose prior to first dose of ribociclib
  • Monoclonal antibodies - at least 3 half-lives since last dose prior to first dose of ribociclib; exception: denosumab for bony metastases is allowable
  • Immunotherapy (e.g. tumor vaccines) - at least 42 days since last dose prior to first dose of ribociclib
  • Radiation - at least 14 days since last dose prior to first dose of ribociclib
• Able to swallow capsules
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky >= 60%)
• Life expectancy > 3 months
• Ability to understand and the willingness to sign a written informed consent document; subject has signed the informed consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements

Exclusion Criteria:

• Subjects with low grade tumors (histologic grade 1/3)

• Histologic diagnosis for which single-agent doxorubicin is NOT appropriate therapy, including but not limited to:

  • Alveolar or embryonal rhabdomyosarcoma
  • Ewings sarcoma or primitive neuroectodermal tumor (PNET)
  • Osteosarcoma
  • Gastrointestinal stromal tumor (GIST)
• Prior systemic therapy with an anthracycline for any indication
• Known hypersensitivity to any of the excipients of ribociclib or doxorubicin (including to peanut and soy)

• Currently receiving any of the following that cannot be discontinued at least 7 days prior to starting study drug:

  • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
  • Medications with a narrow therapeutic window that are predominantly metabolized through CYP3A4/5
  • Herbal supplements, such as St. John's wort; the use of marijuana or its derivatives is allowed in States with statutes permitting the use of recreational or medical marijuana

• Uncontrolled intercurrent medical condition including, but not limited to:

  • Uncontrolled infection
  • Symptomatic congestive heart failure (New York Heart Association [NYHA] class III-IV)
  • Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening
  • Uncontrolled cardiac arrhythmia or arrhythmia requiring medication other than beta blocker
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, etc.)

• Concurrent malignancy or malignancy within 3 years prior to starting study drug, except:

  • Malignancies that have completed therapy and are considered by their physician to be at less than 30% risk of relapse, or
  • Malignancies not requiring treatment (e.g., RAI stage 0 chronic lymphocytic leukemia [CLL])

• Central nervous system (CNS) involvement unless they meet ALL of the following criteria:

  • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
  • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme-inducing anti-epileptic medications for brain metastases
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea/vomiting/diarrhea, malabsorption syndrome, or major small bowel resection)
• Known history of human immunodeficiency virus (HIV) infection (testing not mandatory); NOTE: HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ribociclib; in addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy; appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated
• Systolic blood pressure (SBP) > 160 mmHg or \< 90 mmHg at screening; if initial screening SBP is outside of the eligible range, blood pressure may be re-checked after intervention; SBP must be documented as stable and within the eligible range prior to starting study drug
• Currently receiving rivaroxaban, apixaban, endoxaban, warfarin or other warfarin derived anticoagulant; therapy with heparin, low molecular weight heparin (LMWH), dabigatran or fondaparinux is allowed; if transitioning from a prohibited anticoagulant, a minimum washout of 7 days from last dose of the prohibited medication is required prior to ribociclib start
• Participation in a prior investigational interventional study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
• Major surgery within 14 days prior to starting study drug or has not recovered from surgical complications (tumor biopsy is not considered as major surgery)
• History of congenital long QT syndrome or torsades de pointes
• History of non-compliance to medical regimen or inability to grant consent
• Pregnant or nursing (lactating) women; breastfeeding should be discontinued