Inclusion Criteria:
1. Diagnosis of soft tissue sarcoma or conventional chondrosarcoma, dedifferentiated
chondrosarcoma, 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 the
following requirements must be met:
1. Conventional chondrosarcoma low-grade osteosarcoma, and chordoma: No
requirements regarding prior therapy. 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. If anthracycline
chemotherapy is contraindicated, alternative prior first line chemotherapy is
acceptable.
3. Soft tissue sarcoma: at least 1 line of systemic therapy, unless the sarcoma
subtype is one that is generally considered unresponsive to standard
chemotherapy.
4. Age ≥ 18 years.
5. Provide study specific (step 1) 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. Cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin D3 (CCND3), cyclin dependent
kinase 4 (CDK4), and/or cyclin dependent kinase 6 (CDK6) amplification/copy
number gain. 2. Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) or CDKN2B copy number loss. 7. Provide study-specific (step 2) informed consent. 8. Rb positive confirmed by immunohistochemistry testing of archived tumor tissue
specimen (metastatic or primary site) performed centrally at Medical College of
Wisconsin Precision Medicine Laboratory.
9. All subjects must have measurable disease as defined by RECIST 1.1. (See RECIST 1.1
criteria in Appendix 10.
10. 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).
11. A washout period of at least 21 days is required between last chemotherapy dose and
enrollment.
12. A washout period of at least 14 days is required between end of radiotherapy and
enrollment.
13. At least 14 days after surgery, and absence of significant wound healing issues that
would pose infection risk.
14. Subjects with brain metastasis that have been treated with definitive surgery or
radiation and have been clinically stable for 3 months are eligible.
15. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 16. Adequate organ and marrow function as defined below (ULN indicates institutional
upper limit of normal):
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.
- - 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.
- - Aspartate aminotransferase (AST)(SGOT)/alanine aminotransferase (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 Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) formula), or actual CrCl as determined by 24-hour urine
collection.
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 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.)
18. 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.)
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 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.
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 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.
7. 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.
8. Pregnant women and women who are breast-feeding.
9. Subjects must not have current evidence of another malignancy that requires
treatment.
10. 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.
