دورية أكاديمية

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.

التفاصيل البيبلوغرافية
العنوان: A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors.
المؤلفون: Cash T; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, Georgia, USA., Jonus HC; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA., Tsvetkova M; Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Beumer JH; Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.; Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Sadanand A; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA., Lee JY; Laney Graduate School Cancer Biology Program, Emory University, Atlanta, Georgia, USA., Henry CJ; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, Georgia, USA.; Laney Graduate School Cancer Biology Program, Emory University, Atlanta, Georgia, USA., Aguilera D; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA., Harvey RD; Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, Georgia, USA.; Department of Hematology/Medical Oncology and Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA., Goldsmith KC; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, Georgia, USA.; Laney Graduate School Cancer Biology Program, Emory University, Atlanta, Georgia, USA.
المصدر: Pediatric blood & cancer [Pediatr Blood Cancer] 2023 Aug; Vol. 70 (8), pp. e30405. Date of Electronic Publication: 2023 May 09.
نوع المنشور: Clinical Trial, Phase I; Journal Article
اللغة: English
بيانات الدورية: Publisher: John Wiley Country of Publication: United States NLM ID: 101186624 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1545-5017 (Electronic) Linking ISSN: 15455009 NLM ISO Abbreviation: Pediatr Blood Cancer Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Hoboken, N.J. : John Wiley, c 2004-
مواضيع طبية MeSH: Sarcoma, Ewing* , Neoplasms*/drug therapy , Central Nervous System Neoplasms*/drug therapy , Central Nervous System Neoplasms*/etiology , Neuroectodermal Tumors, Primitive, Peripheral*, Humans ; Child ; Infant ; Child, Preschool ; Adolescent ; Young Adult ; Adult ; Topotecan ; Simvastatin/adverse effects ; Interleukin-6 ; Cyclophosphamide ; Maximum Tolerated Dose ; Antineoplastic Combined Chemotherapy Protocols/adverse effects
مستخلص: Background: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors.
Methods: Simvastatin was administered orally twice daily on days 1-21, with topotecan and cyclophosphamide intravenously on days 1-5 of a 21-day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m 2 /dose, with a de-escalation DL of 100 mg/m 2 /dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1.
Results: The median age of 14 eligible patients was 11.5 years (range: 1-23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose-limiting toxicity (DLT)-evaluable patients received a median of four cycles (range: 1-6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL-6) concentrations (N = 6) showed sustained IL-6 reductions with decrease to normal values by day 21 in all patients, indicating potential on-target effects.
Conclusions: The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m 2 /dose.
(© 2023 Wiley Periodicals LLC.)
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معلومات مُعتمدة: P30 CA047904 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: CNS tumor; pediatric; phase 1; simvastatin; solid tumor; topotecan/cyclophosphamide
المشرفين على المادة: 7M7YKX2N15 (Topotecan)
AGG2FN16EV (Simvastatin)
0 (Interleukin-6)
8N3DW7272P (Cyclophosphamide)
تواريخ الأحداث: Date Created: 20230509 Date Completed: 20230626 Latest Revision: 20240802
رمز التحديث: 20240802
مُعرف محوري في PubMed: PMC11225565
DOI: 10.1002/pbc.30405
PMID: 37158620
قاعدة البيانات: MEDLINE
الوصف
تدمد:1545-5017
DOI:10.1002/pbc.30405