Abemaciclib for Bone and Soft Tissue Sarcoma With Cyclin-Dependent Kinase (CDK) Pathway Alteration

Inclusion Criteria:

1. Diagnosis of soft tissue sarcoma or conventional chondrosarcoma, dedifferentiatedchondrosarcoma, chordoma, or osteosarcoma (see exclusion criteria below)

2. Metastatic or locally advanced disease that is unresectable

3. There is no limit to the number of prior therapies a subject may have had, but thefollowing requirements must be met:

4. Conventional chondrosarcoma low-grade osteosarcoma, and chordoma: Norequirements regarding prior therapy

5. Osteosarcoma (high-grade), Dedifferentiated chondrosarcoma: at least 1 prioranthracycline chemotherapy, alone or in combination, required either asadjuvant, neoadjuvant or in the metastatic setting. If anthracyclinechemotherapy is contraindicated, alternative prior first line chemotherapy isacceptable.

6. Soft tissue sarcoma: at least 1 line of systemic therapy, unless the sarcomasubtype is one that is generally considered unresponsive to standardchemotherapy.

7. Age ≥ 18 years.

8. Provide study specific (step 1) informed consent prior to study entry

9. Documented CDK pathway abnormality on a commercially available mutation profilingtest (Foundation, Tempus xT, etc), if performed previously as part ofroutine/standard care on tumor (metastatic or primary), having at least one of thefollowing (a and/or b)

10. Cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin D3 (CCND3), cyclin dependentkinase 4 (CDK4), and/or cyclin dependent kinase 6 (CDK6) amplification/copynumber gain

11. Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) or CDKN2B copy number loss

12. Provide study-specific (step 2) informed consent

13. Rb positive confirmed by immunohistochemistry testing of archived tumor tissuespecimen (metastatic or primary site) performed centrally at Medical College ofWisconsin Precision Medicine Laboratory.

14. All subjects must have measurable disease as defined by RECIST 1.1. (See RECIST 1.1criteria in Appendix 10.

15. Subjects must also have had evidence of disease progression by RECIST 1.1 within 6months of enrollment, or newly diagnosed within the last 6 months (refer to step 1criteria regarding previous lines of therapy).

16. A washout period of at least 21 days is required between last chemotherapy dose andenrollment.

17. A washout period of at least 14 days is required between end of radiotherapy andenrollment.

18. At least 14 days after surgery, and absence of significant wound healing issues thatwould pose infection risk.

19. Subjects with brain metastasis that have been treated with definitive surgery orradiation and have been clinically stable for 3 months are eligible.

20. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

21. Adequate organ and marrow function as defined below (ULN indicates institutionalupper limit of normal):

• Hemoglobin ≥ 8.0 g/dLa. Patients may receive erythrocyte transfusions to achieve this hemoglobinlevel at the discretion of the investigator. Initial treatment must not beginearlier than the day after the erythrocyte transfusion.

• Platelets ≥ 100 x 10^9/L

• Total bilirubin ≤ 1.5 x ULNa. Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN anddirect bilirubin within normal limits are permitted.

• Aspartate aminotransferase (AST)(SGOT)/alanine aminotransferase (ALT)(SGPT) ≤ 3x 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 Chronic Kidney Disease EpidemiologyCollaboration (CKD-EPI) formula), or actual CrCl as determined by 24-hour urinecollection

17. 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 ofthe above two criteria), must have a negative serum pregnancy test within 21days of step 2 enrollment AND

• Agree to practice two acceptable methods of contraception (combinationmethods requires use of two of the following: diaphragm with spermicide,cervical cap with spermicide, contraceptive sponge, male or female condomwith spermicidal agent added, hormonal contraceptive) from the time ofsigning of the informed consent form through 90 days after the last doseof study agent, OR

• Agree to practice true abstinence when this is in line with the preferredand usual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are notacceptable contraception methods.)

18. Male subjects, even if surgically sterilized (i.e., status post vasectomy), mustagree to one of the following:

• Practice effective barrier contraception during the entire study period andthrough 60 calendar days after the last dose of study agent, OR

• Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, post ovulation methods] and withdrawal are notacceptable methods of contraception.)

19. Subjects must be deemed able to comply with the study plan by the local PI.

20. Ability to swallow oral medications

Exclusion Criteria:

1. Diagnosis of well differentiated (WD) or dedifferentiated (DD) liposarcoma

2. Prior treatment with a specific CDK 4 or CDK 6 inhibitor - (such as palbociclib,abemaciclib, or ribociclib).

3. Subjects who have not recovered (Common Terminology Criteria for Adverse Events [CTCAE v5.0] Grade ≤1) from the acute effects of chemotherapy (except for residualalopecia or Grade 2 peripheral neuropathy) prior to enrollment, or other toxicity orserious preexisting medical condition(s) (for example, interstitial lung disease,severe dyspnea at rest or requiring oxygen therapy, history of major surgicalresection involving the stomach or small bowel, or preexisting Crohn's disease orulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2or higher diarrhea) that in the opinion of the site PI is expected to precludeparticipation in this study.

4. Subjects currently receiving any other investigational agents.

5. Current ongoing treatment with strong Cytochrome P450, family 3, subfamily A (CYP3A)inducers or inhibitors.

6. Uncontrolled intercurrent illness including, but not limited to, known ongoing oractive bacterial infection (requiring IV antibiotics), fungal infection, detectableviral infection (such as known HIV or active hepatitis B or C) (screening tests isnot required for enrollment), symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia (specifically, atrial fibrillation or ventriculardysrhythmias except ventricular premature contractions), or psychiatricillness/social situations that would limit compliance with study requirements.

7. The subject has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest.

8. Pregnant women and women who are breast-feeding.

9. Subjects must not have current evidence of another malignancy that requirestreatment.

10. Subjects who received treatment with live attenuated viruses within 30 days prior toeligibility confirmation or might receive the treatment through the duration of thetrial.