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

  • STATUS
    Recruiting
  • End date
    Sep 1, 2024
  • participants needed
    45
  • sponsor
    Medical College of Wisconsin
Updated on 23 February 2021
renal function
systemic therapy
measurable disease
glomerular filtration rate
kidney function tests
metastasis
neutrophil count
EGFR
blood transfusion
cancer chemotherapy
immunomodulators
soft tissue sarcoma

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.

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

Details
Condition Connective and Soft Tissue Neoplasm, Osteosarcoma, Sarcoma, Chondrosarcoma, All Solid Tumors, Solid Tumors, Sarcoma (Pediatric), Soft Tissue Sarcoma, chondrosarcomas, bone sarcoma, sarcomas, soft tissue sarcomas
Treatment Abemaciclib
Clinical Study IdentifierNCT04040205
SponsorMedical College of Wisconsin
Last Modified on23 February 2021

Eligibility

Yes No Not Sure

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)
Cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin D3 (CCND3), cyclin dependent kinase 4 (CDK4), and/or cyclin dependent kinase 6 (CDK6) amplification
Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) homozygous loss
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
All subjects must have measurable disease as defined by RECIST 1.1. (See RECIST 1.1 criteria in Appendix 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)
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
Eastern Cooperative Oncology Group (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
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
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 Cytochrome P450, family 3, subfamily A (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
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