Chondrosarcoma, Osteosarcoma, Soft Tissue Sarcoma
Conditions
Keywords
Rb, Retinoblastoma, Chondrosarcoma, Osteosarcoma, Soft Tissue Sarcoma
Brief summary
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 twice daily until progression or discontinuation criteria are met.
Detailed description
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 cyclin-dependent kinase 4/6 (CDK4/6) 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 tissue sarcoma. 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
Interventions
DRUGAbemaciclib
Abemaciclib 200 mg will be taken by mouth twice daily.
Sponsors
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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): * 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. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival | 12 weeks | This outcome measure is the number of subjects whose disease has not progressed as defined by RECIST 1.1 criteria. |
Countries
United States
Contacts
CONTACTMedical College of Wisconsin Cancer Center Clinical Trials Office
PRINCIPAL_INVESTIGATORJohn Charlson, MD
Medical College of Wisconsin
Outcome results
None listed