Pegylated Liposomal Doxorubicin Combined with Cyclophosphamide and Vincristine in Pediatric Patients with Relapsed/refractory Solid Tumor: a Single-arm, Open-label, Phase I Study

Overview

Journal EClinicalMedicine

Specialty General Medicine

Date 2024 Jul 15

PMID 39007065

Authors

Suying Lu

Juan Wang

Junting Huang

FeiFei Sun

Jia Zhu

Yi Que

Hui Li

Ying Guo

Ruiqing Cai

Zijun Zhen

Xiaofei Sun

Yizhuo Zhang

Affiliations

Soon will be listed here.

Abstract

Background: The combined vincristine, pegylated liposomal doxorubicin (PLD), and cyclophosphamide (VPC) regimen has never been studied in pediatric patients.

Methods: This open-label, single-center, single-arm phase I study utilizing a "3 + 3" design enrolled children with relapsed/refractory (R/R) solid tumors. Three dose levels of PLD (Duomeisu®) were studied (30, 40, or 50 mg/m) in combination with cyclophosphamide (1500 mg/m), mesna (1500 mg/m), and vincristine (1.5 mg/m, maximum 2 mg) once every 3 weeks. The primary endpoints included safety, the maximum tolerated dose (MTD) of PLD (Duomeisu®), and the recommended phase 2 dose (RP2D) of PLD (Duomeisu®) for further phase 2 investigation. The secondary endpoints were objective response rate (ORR) and disease control rate (DCR). This study is registered with ClinicalTrials.gov, NCT04213612.

Findings: Between January 7, 2020, and November 18, 2021, 34 patients were eligible and evaluable for toxicity, while 26 patients were evaluable for response. The MTD of PLD (Duomeisu®) was 30 mg/m. The most common adverse event (AE) was grade 3 or 4 neutropenia (61.8%). The most common grade 1 or 2 non-hematologic AE and cardiotoxicity effects were vomiting (35.3%) and abnormal electrocardiogram T waves (20.6%), respectively. ORR and DCR to VPC regimen after two cycles were 50.0% and 92.3%, respectively. Targeted gene panel sequencing revealed the activation of mutation may be an adverse prognostic factor.

Interpretation: The VPC regimen showed a promising safety profile and had preliminary efficacy in children with R/R solid tumors. The RP2D for PLD (Duomeisu®) combined with cyclophosphamide and vincristine is 30 mg/m once every 3 weeks.

Funding: CSPC Ouyi Pharmaceutical Co., Ltd., Shijiazhuang, the National Key Research and Development Program of China [No. 2022YFC2705005], the National Natural Science Foundation of China [No. 82203303], and the Basic and Applied Basic Research Foundation of Guangdong Province [No. 2021A1515110234].

References

Judson I, Radford J, Harris M, Blay J, van Hoesel Q, Le Cesne A . Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001; 37(7):870-7. DOI: 10.1016/s0959-8049(01)00050-8. View

Lipshultz S, Scully R, Lipsitz S, Sallan S, Silverman L, Miller T . Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol. 2010; 11(10):950-61. PMC: 3756093. DOI: 10.1016/S1470-2045(10)70204-7. View

Chow E, Chen Y, Kremer L, Breslow N, Hudson M, Armstrong G . Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2014; 33(5):394-402. PMC: 4314592. DOI: 10.1200/JCO.2014.56.1373. View

Wen X, Pan Q, Xu B, Xiao W, Weng D, Zhao J . Phase I study of pegylated liposomal doxorubicin and cisplatin in patients with advanced osteosarcoma. Cancer Chemother Pharmacol. 2022; 89(2):209-215. DOI: 10.1007/s00280-021-04371-6. View

Lipshultz S, Adams M, Colan S, Constine L, Herman E, Hsu D . Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation. 2013; 128(17):1927-95. DOI: 10.1161/CIR.0b013e3182a88099. View

Trudeau M, Clemons M, Provencher L, Panasci L, Yelle L, Rayson D . Phase II multicenter trial of anthracycline rechallenge with pegylated liposomal doxorubicin plus cyclophosphamide for first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines. J Clin Oncol. 2009; 27(35):5906-10. DOI: 10.1200/JCO.2009.22.7504. View

Nielsen O, Reichardt P, Christensen T, Pink D, Daugaard S, Hermans C . Phase 1 European Organisation for Research and Treatment of Cancer study determining safety of pegylated liposomal doxorubicin (Caelyx) in combination with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue.... Eur J Cancer. 2006; 42(14):2303-9. DOI: 10.1016/j.ejca.2006.04.011. View

Heemelaar J, Speetjens F, Al Jaff A, Evenhuis R, Polomski E, Mertens B . Impact of Age at Diagnosis on Cardiotoxicity in High-Grade Osteosarcoma and Ewing Sarcoma Patients. JACC CardioOncol. 2023; 5(1):117-127. PMC: 9982211. DOI: 10.1016/j.jaccao.2022.11.016. View

Munoz A, Maldonado M, Pardo N, Fernandez J, Vela E, Cubells J . Pegylated liposomal doxorubicin hydrochloride (PLD) for advanced sarcomas in children: preliminary results. Pediatr Blood Cancer. 2004; 43(2):152-5. DOI: 10.1002/pbc.20029. View

10.

Lenihan D, Cardinale D . Late cardiac effects of cancer treatment. J Clin Oncol. 2012; 30(30):3657-64. DOI: 10.1200/JCO.2012.45.2938. View

11.

Rau K, Lin Y, Chen Y, Chen J, Lee K, Wang C . Pegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study. BMC Cancer. 2015; 15:423. PMC: 4440506. DOI: 10.1186/s12885-015-1433-4. View

12.

Hamanishi J, Takeshima N, Katsumata N, Ushijima K, Kimura T, Takeuchi S . Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA). J Clin Oncol. 2021; 39(33):3671-3681. PMC: 8601279. DOI: 10.1200/JCO.21.00334. View

13.

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

14.

Wouters K, Kremer L, Miller T, Herman E, Lipshultz S . Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005; 131(5):561-78. DOI: 10.1111/j.1365-2141.2005.05759.x. View

15.

Brennan B, Kirton L, Marec-Berard P, Gaspar N, Laurence V, Martin-Broto J . Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet. 2022; 400(10362):1513-1521. DOI: 10.1016/S0140-6736(22)01790-1. View

16.

Fujisaka Y, Horiike A, Shimizu T, Yamamoto N, Yamada Y, Tamura T . Phase 1 clinical study of pegylated liposomal doxorubicin (JNS002) in Japanese patients with solid tumors. Jpn J Clin Oncol. 2006; 36(12):768-74. DOI: 10.1093/jjco/hyl109. View

17.

Miller K, Siegel R, Lin C, Mariotto A, Kramer J, Rowland J . Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016; 66(4):271-89. DOI: 10.3322/caac.21349. View

18.

Marina N, Cochrane D, Harney E, Zomorodi K, Blaney S, Winick N . Dose escalation and pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in children with solid tumors: a pediatric oncology group study. Clin Cancer Res. 2002; 8(2):413-8. View

19.

Trucco M, Meyer C, Thornton K, Shah P, Chen A, Wilky B . A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas. Clin Sarcoma Res. 2018; 8:21. PMC: 6217787. DOI: 10.1186/s13569-018-0107-9. View

20.

Shern J, Selfe J, Izquierdo E, Patidar R, Chou H, Song Y . Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium. J Clin Oncol. 2021; 39(26):2859-2871. PMC: 8425837. DOI: 10.1200/JCO.20.03060. View