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Circulating tumor cells and biomarker modulation with olaratumab monotherapy followed by olaratumab plus doxorubicin: phase 1b study in soft tissue sarcoma patients
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2020-11-11 , DOI: 10.1158/1535-7163.mct-20-0441
Javier Martín-Broto 1 , Antonio López Pousa 2 , Andrew S Brohl 3 , Brian A Van Tine 4 , Benjamin Powers 5 , Silvia Stacchiotti 6 , Jean-Yves Blay 7 , James S Hu 8 , Gerard J Oakley 9 , Hong Wang 9 , Anna M Szpurka 9 , Donna E Levy 10 , Gary Mo 9, 11 , Matteo Ceccarelli 12 , Robin L Jones 13
Affiliation  

This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1–2; 15 mg/kg, cycles 3–7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRβ [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRβ, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.

中文翻译:

循环肿瘤细胞和生物标志物调节与 olaratumab 单药治疗后 olaratumab 加多柔比星:软组织肉瘤患者的 1b 期研究

这项 Ib 期研究列举了全血循环肿瘤细胞 (CTC) 并评估了潜在可切除软组织肉瘤 (STS) 患者的生物标志物,这些患者接受了 olaratumab 单药治疗 (20 mg/kg) 一个周期,然后最多六个周期的 olaratumab。 20 mg/kg,第 1–2 个周期;15 mg/kg,第 3–7 个周期)加多柔比星(第 1 天为 75 mg/m2)。对奥拉单抗单药治疗前后肿瘤组织中的 CTC、血小板衍生生长因子受体 (PDGFR) 和 PDGF 配体表达进行了评估。评估了抗肿瘤活性、安全性、药代动力学和 PET/生物标志物与临床结果的关联。在 51 名接受治疗的患者中,分别有 35、43 和 37 名可评估 CTC 计数、PDGFR 和 PDGF 配体表达。观察到第 1 周期第 8 天的 CTC 增加,随后在第 3 周期第 1 天或第 30 天的随访中显着减少。在疾病控制的患者中,奥拉单抗单药治疗后 CTC 计数的减少高于疾病未控制的患者(57.9% 与 31.2%)。大多数患者的基线 IHC 表达对 PDGFRα [n = 31 (72.1%)] 和 PDGFRβ [n = 36 (83.7%)] 呈阳性。olaratumab 单药治疗后观察到类似的比率 [PDGFRα,n = 30 (69.8%);PDGFRβ,n = 33 (76.7%)]。11 名患者 (29.7%) 在第 2 周期通过 RT-PCR 显示 PDGFRα 减少 30%。PDGFR 表达和 PET 反应显示与临床结果无关。安全性和药代动力学特征与之前的报告一致。这项研究首次使用经过验证的 CTC 检测方法,证实了 STS 中的 CTC 枚举是可行的。然而,
更新日期:2020-11-11
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