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)。
- 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
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.
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。
METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
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.
METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.