Chordoma is a rare bone tumor with slow growth. The standard treatment is en-bloc excision, but the site of origin of the disease (skull base, sacrum) often prevents complete resection. For these patients, debulking surgery followed by radiation therapy (RT) or high-dose RT alone can be an alternative. However, local relapses and, more rarely, metastatic disease occur, and there is no efficient systemic therapy available. Only very limited responses are seen with chemotherapy or targeted agents (e.g. imatinib, lapatinib). In chordoma cell lines and patient biopsies, the p16 (cyclin-dependent kinase inhibitor 2a, encoded by CDKN2A) tumor suppressor is consistently deleted. Experiments with patient-derived chordoma cell lines demonstrated aberrant CDK4/6 activity downstream of p16 loss, which can be efficiently inhibited by the CDK4/6 inhibitor palbociclib, resulting in reduced proliferation and growth of neoplastic cells (von Witzleben et al. Cancer Res 2015;75(18):3823-31).
Patients ≥18 years of age with locally advanced or metastatic chordoma with at least one measurable tumor lesion, ECOG Performance Status 0-2, adequate organ function, and loss of p16 (as determined by immunohistochemistry) or CDKN2A (as determined by genetic analysis) who have no response or have lost response to treatment with a tyrosine kinase inhibitor are eligible. Key exclusion criteria are prior treatment with palbociclib, uncontrolled CNS involvement, cytopenia/s, significant cardiovascular disease including prolongation of the corrected QTc interval >470 ms. Based on previous experience with 125 mg palbociclib once daily for 21 days followed by 7 days of rest in patients with other solid-organ malignancies, this regimen is chosen. Based on a Simon optimal 2-stage design, the disease control rate is the primary endpoint, whereby response is defined as complete response, partial response, or stable disease according to RECIST v1.1 after 6 cycles. For sample size calculation, we estimate a poor response with 10% and a good response with 25% (power, 80%; alpha, 5%), resulting in a first stage of 18 patients and, if 3 or more patients respond, a second stage with 25 additional patients (total, n = 43).
Clinical trial identification
NCT03110744 EudraCT Number: 2016-004660-19
Legal entity responsible for the study
University Hospital Heidelberg
NCT Heidelberg, Pfizer
R. Schlenk: Research funding: Novartis, Pfizer, Amgen, AtraZeneca, PharmaMar Speakers bureau: Novartis, Pfizer Advisory board: Daiichi Sankyo, Novartis, Pfizer. All other authors have declared no conflicts of interest.