A study protocol for an open-label, single-arm, single-center phase I clinical study on tolerability, safety, and efficacy of dalpiciclib combined with apatinib in the treatment of patients with advanced or metastatic sarcoma

IntroductionThe prognosis of patients with advanced or metastatic sarcoma is very poor, and a new strategy for patients who fail systemic treatment is urgently required. Apatinib is a small molecule tyrosine kinase inhibitor of VEGFR-2, which can exert an antitumor effect by blocking downstream PI3K/AKT and VEGFR2/STAT3 signaling pathways of sarcoma. Dysregulation of the cyclin D (CCND)-cyclin-dependent kinase 4/6 (CDK4/6)-retinoblastoma 1 (Rb) pathway is highly prevalent in sarcoma. Thus, blocking VEGFR2 and CDK4/6 may exert a synergistic effect. We hypothesize that a combination of apatinib and dalpiciclib, an oral, highly effective, and selective small molecule CDK4/6 inhibitor, may result in higher antitumor efficacy in patients with refractory sarcoma.MethodsIn this open-label, single-arm, single-center phase I trial, participants diagnosed with sarcoma who failed standard systemic treatment will be enrolled. Dose escalation will be conducted into three groups according to traditional 3 + 3 principle: dose 1, dalpiciclib 100 mg once daily oral d1-21+ apatinib 250 mg once daily oral d1-28, every 28 days as one cycle; dose 2, dalpiciclib 100 mg d1-21+ apatinib 500 mg d1-28; dose 3, dalpiciclib 150 mg d-21+ apatinib 500 mg d1-28. The primary endpoint is the safety and tolerability of combined treatment. The secondary endpoint is to evaluate the initial efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS).DiscussionThis trial will provide evidence of the tolerability, safety, and efficacy of dalpiciclib in combination with apatinib in metastatic sarcoma patients who have failed first-line systemic treatment. In sarcomas, Apatinib and dalpiciclib may exert cell cycle control and antitumor synergistic effects by inhibiting the downstream PI3K/AKT pathway and blocking the CDKN2A -CCND-CDK4/6-RB pathway, respectively.image