This is a single-arm, phase II study that will enroll a total of 45 subjects. All subjects
will have a confirmed diagnosis of metastatic or unresectable soft tissue sarcoma or bone
sarcoma. All subjects must have intact Rb, identified at the time of screening, by
immunohistochemistry testing of submitted tumor specimen. Subjects will receive Abemaciclib
200 mg BID until progression or discontinuation criteria are met.
Population to be studied:
Since abemaciclib is already being studied in dedifferentiated liposarcoma patients, patients
with this sarcoma subtype will not be enrolled in the current study. This exploratory study
will enroll patients with all other types of soft tissue sarcoma, in addition to patients
with several bone sarcomas. We are testing the hypothesis that biomarkers of Cyclin D1 -
CDK4/6 - Rb pathway activation will identify patients with a rare, heterogeneous cancer who
are most likely to benefit from CDK 4/6 inhibition with abemaciclib.
There will be three cohorts of patients, intended to ensure representation of subjects with
rare bone sarcomas - chondrosarcoma and osteosarcoma - that have relatively frequent
occurrence of abnormalities in the Cyclin D1 - CDK4/6 - Rb pathway, in addition to soft
Cohort 1 - Conventional chondrosarcoma, 9-12 patients; Cohort 2 - Osteosarcoma,
Dedifferentiated chondrosarcoma, 9-12 patients; Cohort 3 - Soft tissue sarcoma (except WD/DD
Liposarcoma), 22-26 patients
1. Diagnosis of soft tissue sarcoma or conventional chondrosarcoma, dedifferentiated
chondrosarcoma, 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 the
following requirements must be met:
1. Conventional chondrosarcoma and low-grade osteosarcoma: No requirements regarding
2. 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.
3. Soft tissue sarcoma: at least 1 line of systemic therapy, unless the sarcoma
subtype is one that is generally considered unresponsive to standard
4. Age ≥ 18 years.
5. Provide study specific informed consent prior to study entry
6. 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)
1. CCND1, CCND2, CCND3, CDK4, and/or CDK6 amplification
2. CDKN2A homozygous loss
7. Rb positive confirmed by immunohistochemistry testing of archived tumor tissue
specimen (metastatic or primary site) performed centrally at MCW Precision Medicine
8. All subjects must have measurable disease as defined by RECIST 1.1. (See RECIST 1.1
criteria in Appendix 10.
9. 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).
10. A washout period of at least 21 days is required between last chemotherapy dose and
11. A washout period of at least 14 days is required between end of radiotherapy and
12. At least 14 days after surgery, and absence of significant wound healing issues that
would pose infection risk.
13. Subjects with brain metastasis that have been treated with definitive surgery or
radiation and have been clinically stable for 3 months are eligible.
14. ECOG performance status 0 or 1
15. 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
a. 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
a. 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 m2 (MDRD or CKD-EPI formula), or actual CrCl as determined by
24-hour urine collection
16. 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.)
17. 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
18. Subjects must be deemed able to comply with the study plan by the local PI.
19. Ability to swallow oral medications
1. Diagnosis of well differentiated (WD) or dedifferentiated (DD) liposarcoma
2. Any bone sarcoma other than osteosarcoma, conventional or dedifferentiated
3. Prior treatment with a specific CDK 4 or CDK 6 inhibitor - (such as palbociclib,
abemaciclib, or ribociclib).
4. 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
5. Subjects currently receiving any other investigational agents.
6. Current ongoing treatment with strong CYP3A inducers or inhibitors.
7. 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.
8. 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
9. Pregnant women and women who are breast-feeding.
10. Subjects must not have current evidence of another malignancy that requires treatment.
11. 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