A Phase I Study of Irinotecan and Temozolomide with Bevacizumab in Children with Recurrent/refractory Central Nervous System Tumors

Overview

Journal Childs Nerv Syst

Specialty Pediatrics

Date 2022 Mar 9

PMID 35260913

Authors

Jonathan Metts

Brittany Harrington

Emad Salman

Scott M Bradfield

Jennifer Flanary

Maua Mosha

Ernest Amankwah

Stacie Stapleton

Affiliations

Soon will be listed here.

Abstract

Purpose: Children with relapsed/refractory central nervous system (CNS) tumors require novel combinations of therapies. Irinotecan and temozolomide (IT) is a frequently used therapy with an established toxicity profile. Bevacizumab is an anti-VEGF monoclonal antibody with demonstrated activity in CNS tumors. Therefore, the combination of these agents has therapeutic potential in CNS tumors. The objective of this study was to determine the maximum tolerated dose (MTD) of escalating dose IT combined with a fixed dose of bevacizumab (BIT) in children with relapsed/refractory CNS tumors.

Methods: A phase I trial was performed in a 3 + 3 design. Therapy toxicities and radiologic responses to treatment were described.

Results: One hundred eighty cycles of therapy were administered to 26 patients. The MTD of BIT was dose level 1, (bevacizumab 10 mg/kg on days 1 and 15, irinotecan 125 mg/m on days 1 and 15, and temozolomide 125 mg/m on days 1-5 of 28-day cycles). The regimen was well tolerated with primarily hematologic toxicity, which was not dose limiting. Among 22 response-evaluable patients, there was 1 complete response (CR), 6 partial responses (PR), and 10 stable diseases (SD) with an overall response rate (ORR: CR + PR) of 31.8%.

Conclusion: At the MTD, BIT therapy was well tolerated, and prolonged treatment courses of up to 24 cycles were feasible, with radiographic responses observed. Further evaluation is needed for efficacy in a phase II trial (NCT00876993, registered April 7, 2009, www.

Clinicaltrials: gov ).

Citing Articles

Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis.

Spini A, Ciccone V, Rosellini P, Ziche M, Lucenteforte E, Salvo F Cancers (Basel). 2022; 14(21).

PMID: 36358734 PMC: 9654149. DOI: 10.3390/cancers14215315.

References

Ostrom Q, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan J . CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol. 2021; 23(12 Suppl 2):iii1-iii105. PMC: 8491279. DOI: 10.1093/neuonc/noab200. View

Johnston D, Keene D, Strother D, Taneva M, Lafay-Cousin L, Fryer C . Survival Following Tumor Recurrence in Children With Medulloblastoma. J Pediatr Hematol Oncol. 2018; 40(3):e159-e163. DOI: 10.1097/MPH.0000000000001095. View

Koschmann C, Bloom K, Upadhyaya S, Geyer J, Leary S . Survival After Relapse of Medulloblastoma. J Pediatr Hematol Oncol. 2016; 38(4):269-73. DOI: 10.1097/MPH.0000000000000547. View

Broniscer A, Gajjar A . Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist. 2004; 9(2):197-206. DOI: 10.1634/theoncologist.9-2-197. View

Turner C, Gururangan S, Eastwood J, Bottom K, Watral M, Beason R . Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience. Neuro Oncol. 2002; 4(2):102-8. PMC: 1920653. DOI: 10.1093/neuonc/4.2.109. View

Vassal G, Doz F, Frappaz D, Imadalou K, Sicard E, Santos A . A phase I study of irinotecan as a 3-week schedule in children with refractory or recurrent solid tumors. J Clin Oncol. 2003; 21(20):3844-52. DOI: 10.1200/JCO.2003.08.175. View

Fouladi M, Nicholson H, Zhou T, Laningham F, Helton K, Holmes E . A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study. Cancer. 2007; 110(11):2535-41. DOI: 10.1002/cncr.23078. View

Balmaceda C, Peereboom D, Pannullo S, Cheung Y, Fisher P, Alavi J . Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas. Cancer. 2008; 112(5):1139-46. DOI: 10.1002/cncr.23167. View

Barone G, Maurizi P, Tamburrini G, Riccardi R . Role of temozolomide in pediatric brain tumors. Childs Nerv Syst. 2006; 22(7):652-61. DOI: 10.1007/s00381-006-0081-z. View

10.

Norris R, Shusterman S, Gore L, Muscal J, Macy M, Fox E . Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors. Pediatr Blood Cancer. 2014; 61(10):1792-7. DOI: 10.1002/pbc.25105. View

11.

von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett T, Rizzari C . Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016; 34(36):4381-4389. DOI: 10.1200/JCO.2016.67.3301. View

12.

Gururangan S, Fangusaro J, Poussaint T, Onar-Thomas A, Gilbertson R, Vajapeyam S . Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a Pediatric Brain Tumor Consortium study. Neuro Oncol. 2012; 14(11):1404-12. PMC: 3480265. DOI: 10.1093/neuonc/nos213. View

13.

Glade Bender J, Yamashiro D, Fox E . Clinical development of VEGF signaling pathway inhibitors in childhood solid tumors. Oncologist. 2011; 16(11):1614-25. PMC: 3233297. DOI: 10.1634/theoncologist.2011-0148. View

14.

Venkatramani R, Malogolowkin M, Davidson T, May W, Sposto R, Mascarenhas L . A phase I study of vincristine, irinotecan, temozolomide and bevacizumab (vitb) in pediatric patients with relapsed solid tumors. PLoS One. 2013; 8(7):e68416. PMC: 3718768. DOI: 10.1371/journal.pone.0068416. View

15.

Friedman H, Prados M, Wen P, Mikkelsen T, Schiff D, Abrey L . Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009; 27(28):4733-40. DOI: 10.1200/JCO.2008.19.8721. View

16.

Mamdouhi T, Desai P, Goodman H, Amodio J, Edelman M, Rich B . Comment on: Discrepancies between F-18-FDG PET/CT findings and conventional imaging in Langerhans cell histiocytosis. Pediatr Blood Cancer. 2021; 69(5):e29504. DOI: 10.1002/pbc.29504. View

17.

Crotty E, Leary S, Geyer J, Olson J, Millard N, Sato A . Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience. J Neurooncol. 2020; 148(3):607-617. DOI: 10.1007/s11060-020-03558-w. View

18.

Schiavetti A, Varrasso G, Mollace M, Dominici C, Ferrara E, Papoff P . Bevacizumab-containing regimen in relapsed/progressed brain tumors: a single-institution experience. Childs Nerv Syst. 2019; 35(6):1007-1012. DOI: 10.1007/s00381-019-04117-z. View

19.

Sait S, Pandit-Taskar N, Modak S . Failure of MIBG scan to detect metastases in SDHB-mutated pediatric metastatic pheochromocytoma. Pediatr Blood Cancer. 2017; 64(11). DOI: 10.1002/pbc.26549. View

20.

Salloum R, Hummel T, Kumar S, Dorris K, Li S, Lin T . A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study. J Neurooncol. 2016; 129(3):443-451. PMC: 5288808. DOI: 10.1007/s11060-016-2189-7. View