Inclusion Criteria:

• Diagnosis of soft tissue sarcoma or conventional chondrosarcoma, dedifferentiated chondrosarcoma, osteosarcoma (see exclusion criteria below).
• Metastatic or locally advanced disease that is unresectable.
• There is no limit to the number of prior therapies a subject may have had, but the following requirements must be met:
  • Conventional chondrosarcoma and low-grade osteosarcoma: No requirements regarding prior therapy;
  • Osteosarcoma (high-grade), Dedifferentiated chondrosarcoma: at least 1 prior anthracycline chemotherapy, alone or in combination, required either as adjuvant, neoadjuvant or in the metastatic setting;
  • Soft tissue sarcoma: at least 1 line of systemic therapy, unless the sarcoma subtype is one that is generally considered unresponsive to standard chemotherapy.
• Age ≥ 18 years.
• Provide study specific informed consent prior to study entry.
• Documented CDK pathway abnormality on a commercially available mutation profiling test (Foundation, Tempus xT, etc), if performed previously as part of routine/standard care on tumor (metastatic or primary), having at least one of the following (a and/or b):
  • CCND1, CCND2, CCND3, CDK4, and/or CDK6 amplification;
  • CDKN2A homozygous loss.
• Rb positive confirmed by immunohistochemistry testing of archived tumor tissue specimen (metastatic or primary site) performed centrally at MCW Precision Medicine Laboratory.
• All subjects must have measurable disease as defined by RECIST 1.1.
• Subjects must also have had evidence of disease progression by RECIST 1.1 within 6 months of enrollment, or newly diagnosed within the last 6 months (refer to step 1 criteria regarding previous lines of therapy).
• A washout period of at least 21 days is required between last chemotherapy dose and enrollment.
• A washout period of at least 14 days is required between end of radiotherapy and enrollment.
• At least 14 days after surgery, and absence of significant wound healing issues that would pose infection risk.
• Subjects with brain metastasis that have been treated with definitive surgery or radiation and have been clinically stable for 3 months are eligible.
• ECOG performance status 0 or 1.
• Adequate organ and marrow function as defined below (ULN indicates institutional upper limit of normal):
  • Absolute neutrophil count ≥ 1.5 x 10^9/L;
  • Hemoglobin ≥ 8.0 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion;
  • Absolute neutrophil count ≥ 1.5 x 10^9/L;
  • Platelets ≥ 100 x 10^9/L;
  • Total bilirubin ≤ 1.5 x ULN. Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted;
  • AST(SGOT)/ALT(SGPT) ≤ 3 x institutional ULN;
  • Renal function (at least one of the following):
    • Estimated Creatinine Clearance (CrCl) ≥ 30 mL/min (Cockcroft-Gault), estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m^2 (MDRD or CKD-EPI formula) or actual CrCl as determined by 24-hour urine collection. 
• Female subjects must meet one of the following:
  • Postmenopausal for at least one year before enrollment; OR
  • Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy); OR
  • If subject is of childbearing potential (defined as not satisfying either of the above two criteria), must have a negative serum pregnancy test within 21 days of step 2 enrollment; AND
  • Agree to practice two acceptable methods of contraception (combination methods requires use of two of the following: diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom with spermicidal agent added, hormonal contraceptive) from the time of signing of the informed consent form through 90 days after the last dose of study agent; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable contraception methods.).
• Male subjects, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:
  • Practice effective barrier contraception during the entire study period and through 60 calendar days after the last dose of study agent; OR
  • Agree to practice 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.).
• Subjects must be deemed able to comply with the study plan by the local PI.
• Ability to swallow oral medications.

Exclusion Criteria:

• Diagnosis of well differentiated (WD) or dedifferentiated (DD) liposarcoma.
• Any bone sarcoma other than osteosarcoma, conventional or dedifferentiated chondrosarcoma.
• Prior treatment with a specific CDK 4 or CDK 6 inhibitor - (such as palbociclib, abemaciclib, or ribociclib).
• Subjects who have not recovered (Common Terminology Criteria for Adverse Events [CTCAE v5.0] Grade ≤1) from the acute effects of chemotherapy (except for residual alopecia or Grade 2 peripheral neuropathy) prior to enrollment, or other toxicity or serious preexisting medical condition(s) (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea) that in the opinion of the site PI is expected to preclude participation in this study.
• Subjects currently receiving any other investigational agents.
• Current ongoing treatment with strong CYP3A inducers or inhibitors.
• Uncontrolled intercurrent illness including, but not limited to, known ongoing or active bacterial infection (requiring IV antibiotics), fungal infection, detectable viral infection (such as known HIV or active hepatitis B or C) (screening tests is not required for enrollment), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (specifically, atrial fibrillation or ventricular dysrhythmias except ventricular premature contractions), or psychiatric illness/social situations that would limit compliance with study requirements.
• The subject has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
• Pregnant women and women who are breast-feeding.
• Subjects must not have current evidence of another malignancy that requires treatment.
• Subjects who received treatment with live attenuated viruses within 30 days prior to eligibility confirmation or might receive the treatment through the duration of the trial.