Background: Soft tissue sarcomas (STS) are a heterogeneous group of tumors, and approximately 40-50% of patients with STS develop metastatic disease. The median overall survival of those patients was 12 months and their 5-year survival rate was 8%. Therefore, study on more effective treatment, especially the targeting therapies, is urgently needed. Objective: To evaluate the efficacy and safety of Endostar® combined with chemotherapy in patients with advanced STS. Methods: A retrospective case-series study was conducted in Cancer Institute of PLA, Xinqiao Hospital. A total of 71 patients suffering from advanced STS (IIB -IV) were included, of whom 49 cases treated with chemotherapy alone were defined as the control group and the rest 22 cases treated with the traditional chemotherapy combined with Endostar® were defined as the test group. The short-term therapeutic effects including objective response rate (ORR), disease control rate (DCR) and safety were evaluated in the two groups. In the follow-up, progression-free survival (PFS) and overall survival (OS) were also observed. Results: In the test and control groups, the ORR was 18.2% and 12.2%, respectively (P = 0.767), and the DCR was 86.4% and 61.2%, respectively (P=0.034). The median time to progression in the test and control groups was 120 days and 70 days with significant difference (P = 0.017), while the median overall survival was 452 days and 286 days without significant difference (P = 0.503). The one-year survival rate in the test group and control group was 56.2% and 35.4%, respectively, while the two-year survival rate was 30.2% and 26.5%, respectively. No significant difference in the side effects was found between the two groups. Conclusions: Endostar® combined with chemotherapy resulted in a higher DCR and longer PFS in the patients with advanced STS, and the toxicity was tolerable.
3503 Background: Akt facilitates cell proliferation/survival and is a suspected driver of progression in ST. MK-2206, a highly selective non-ATP competitive allosteric Akti, has nM IC50 and broad preclinical antitumor activity. Methods: Safety and tolerability of MK-2206 administered QOD in 28-day cycles (cy) was assessed. Doses evaluated: 30, 60, 90 mg, and 75 mg. Main eligibility criteria: ≥18 yo, evaluable advanced ST, ECOG ≤1, HbA1c ≤8% or fasting glucose ≤110% upper limit of normal. PK and phosphorylated Akt (pAkt) in whole blood by meso-scale ELISA were measured. Sequential tumor biopsies were performed in a subset of pts. Results: Dose escalation occurred in 19 pts (8 female/11 male; median age 57 yo; ECOG 0/1: 5/14) and 37 cy of therapy with no DLTs at 30 and 60 mg. CTCAE G3/4 skin rash and CTCAE G3 mucositis were observed at 90 mg in 4/7 pts. After further accrual at 60 mg confirmed safety at this dose, 75 mg was explored; however, 2/3 pts experienced DLT of rash. Dose escalation is complete; the MTD of MK-2206 is 60 mg QOD. Common drug-related AEs included skin (47.1%), gastrointestinal (41.2%), and general disorders (29.4%). AUC0–48hr and Cmax were dose proportional up to 60 mg. Median Tmax is 6 hrs and mean t1/2 ranged from 63 to 76 hr. MK-2206 concentrations exceeding a preliminary, statistically determined PK target of approximately 50–65 nM for significant pAkti in blood were maintained over the entire dosing interval in all patients in the 60 mg cohort. Evidence of PD activity included decreases in whole blood pAkt at all dose levels, reversible CTCAE G1/2 hyperglycemia and CTCAE G1 insulin c-peptide elevations. RECIST stable disease following 2 cycles of therapy was observed in 1 pt at 30 mg and 5 pts at 60 mg. Observed clinical activity included: central tumor necrosis, decreased ascites and peripheral edema, reduction in index lesions, normalization of LFTs, and decreased CA-125. Conclusions: MK-2206 is generally well tolerated at doses up to 60 mg QOD with plasma concentrations that portend activity in preclinical models. PK/PD data suggest a substantial and maintained target inhibition at 60 mg. [Table: see text]
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