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Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children's Oncology Group Phase 1 Consortium study (ADVL1411).

Talazoparib联合替莫唑胺治疗儿童和青少年难治性/复发性实体瘤包括尤文肉瘤的 1/2 期试验: 一项儿童肿瘤学组 1 期联盟研究 (ADVL1411)。

  • 影响因子:2.28
  • DOI:10.1002/pbc.28073
  • 作者列表:"Schafer ES","Rau RE","Berg SL","Liu X","Minard CG","Bishop AJR","Romero JC","Hicks MJ","Nelson MD Jr","Voss S","Reid JM","Fox E","Weigel BJ","Blaney SM
  • 发表时间:2020-02-01
Abstract

PURPOSE:We conducted a phase 1/2 trial of the poly(ADP-ribose) polymerase 1/2 inhibitor talazoparib in combination with low-dose temozolomide (TMZ) to determine the dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetics of this combination in children with recurrent/refractory solid tumors; and to explore clinical activity in Ewing sarcoma (EWS) (NCT02116777). METHODS:Talazoparib (400-600 µg/m2 /dose, maximum daily dose 800-1000 µg) was administered q.d. or b.i.d. orally on day 1 followed by q.d. dosing concomitant with q.d. dosing of oral TMZ (20-55 mg/m2 /day) on days 2 to 6, every 28 days. RESULTS:Forty patients, aged 4 to 25 years, were enrolled. Talazoparib was increased to 600 µg/m2 /dose b.i.d. on day 1, and q.d. thereafter, with 20 mg/m2 /day of TMZ, without DLTs. TMZ was subsequently increased, during which dose-limiting neutropenia and thrombocytopenia occurred in two of three subjects at 55 mg/m2 /day, two of six subjects at 40 mg/m2 /day, and one of six subjects at 30 mg/m2 /day. During dose-finding, two of five EWS and four of 25 non-EWS subjects experienced prolonged stable disease (SD), and one subject with malignant glioma experienced a partial response. In phase 2, 0 of 10 EWS subjects experienced an objective response; two experienced prolonged SD. CONCLUSIONS:Talazoparib and low-dose TMZ are tolerated in children with recurrent/refractory solid tumors. Reversible neutropenia and thrombocytopenia were dose limiting. The RP2D is talazoparib 600 µg/m2 b.i.d. on day 1 followed by 600 µg/m2 q.d. on days 2 to 6 (daily maximum 1000 µg) in combination with temozolomide 30 mg/m2 /day on days 2 to 6. Antitumor activity was not observed in EWS, and limited antitumor activity was observed in central nervous system tumors.

摘要

目的: 我们进行了聚 (ADP-核糖) 聚合酶 1/2 抑制剂talazoparib联合低剂量替莫唑胺 (TMZ) 的 1/2 期试验确定该联合用药在复发/难治性实体瘤患儿中的剂量限制性毒性 (DLTs) 、推荐 2 期剂量 (RP2D) 和药代动力学; 并探讨尤文肉瘤 (EWS) 的临床活性(NCT02116777)。 方法: 给予Talazoparib (400-600 µ g/m2/剂量,最大日剂量 800-1000 µ g) q.d.或者b.i.d.第 1 天口服,随后q.d.与q.d.同时给药。口服TMZ (20-55 mg/m2/天) 给药第 2-6 天,每 28 天。 结果: 入组 40 例患者,年龄 4 ~ 25 岁。Talazoparib增加至 600 µ g/m2/剂量b.i.d.在第 1 天,和q.d.此后,用 20 mg/m2/天的TMZ,无DLTs。TMZ随后增加,在此期间,剂量限制性中性粒细胞减少和血小板减少症发生在 3 例受试者中的 2 例 (55 mg/m2/天),6 例受试者中的 2 例 (40 mg/m2/天),和 6 名受试者之一,30 mg/m2/天。在剂量发现期间,5 例EWS受试者中的 2 例和 25 例非EWS受试者中的 4 例经历了长期稳定的疾病 (SD),1 例恶性胶质瘤受试者经历了部分反应。在第 2 阶段,10 例EWS受试者中有 0 例经历了客观反应; 2 例经历了延长的SD。 结论: Talazoparib和低剂量TMZ在复发/难治性实体瘤患儿中是耐受的。可逆性中性粒细胞减少和血小板减少症是剂量限制性的。RP2D为talazoparib 600 µ g/m2 b.i.d.在第 1 天,随后是 600 µ g/m2 q.d.在第 2 至 6 天 (每日最大 1000 µ g) 联合替莫唑胺 30 mg/m2/天,在第 2 至 6 天。在EWS中未观察到抗肿瘤活性,在中枢神经系统肿瘤中观察到有限的抗肿瘤活性。

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DOI:10.1259/bjr.20180883
作者列表:["Tran S","Puric E","Walser M","Poel R","Datta NR","Heuberger J","Pica A","Marder D","Lomax N","Bolsi A","Morach P","Bachtiary B","Seddon BM","Schneider R","Bodis S","Weber DC"]

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影响因子:1.41
发表时间:2020-03-01
DOI:10.1177/1078155219842277
作者列表:["Gyori DJ","Bullington SM","Crawford BS","Vernon VP"]

METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.

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影响因子:2.83
发表时间:2020-01-01
DOI:10.1007/s00520-019-04843-9
作者列表:["Dohzono S","Sasaoka R","Takamatsu K","Hoshino M","Nakamura H"]

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骨肿瘤方向

骨肿瘤是发生于骨骼或其附属组织的肿瘤。有良性,恶性之分,良性骨肿瘤易根治,预后良好,恶性骨肿瘤发展迅速,预后不佳,死亡率高。

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