Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma

Stephanie Vairy, Gwénaël Le Teuff, Francisco Bautista, Emilie De Carli, Anne-Isabelle Bertozzi, Anne Pagnier, Fanny Fouyssac, Karsten Nysom, Isabelle Aerts, Pierre Leblond, Frederic Millot, Claire Berger, Sandra Canale, Angelo Paci, Vianney Poinsignon, Aurelie Chevance, Monia Ezzalfani, Dominique Vidaud, Angela Di Giannatale, Raquel Hladun-Alvaro, Francois M Petit, Gilles Vassal, Birgit Geoerger, Marie-Cécile Le Deley, Jacques Grill, Stephanie Vairy, Gwénaël Le Teuff, Francisco Bautista, Emilie De Carli, Anne-Isabelle Bertozzi, Anne Pagnier, Fanny Fouyssac, Karsten Nysom, Isabelle Aerts, Pierre Leblond, Frederic Millot, Claire Berger, Sandra Canale, Angelo Paci, Vianney Poinsignon, Aurelie Chevance, Monia Ezzalfani, Dominique Vidaud, Angela Di Giannatale, Raquel Hladun-Alvaro, Francois M Petit, Gilles Vassal, Birgit Geoerger, Marie-Cécile Le Deley, Jacques Grill

Abstract

Background: New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation.

Methods: This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922).

Results: Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67).

Conclusions: Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

Keywords: Gilbert disease; neurofibromatosis type 1; pharmacogenomics; pharmacokinetics; pilocytic astrocytoma.

© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Figures

Figure 1.
Figure 1.
Individual description of the course of treatment for the 35 enrolled patients according to the dose level of nilotinib and vinblastine. DLT, dose-limiting toxicity; MR, minor response; SD, stable disease; PD, progressive disease; PR, partial response.
Figure 2
Figure 2
Kaplan–Meier curves of 5 years progression-free survival (dashed line) and 5 years overall survival (solid line) during the study for the 35 enrolled patients.

References

    1. Stiller CA, Nectoux J. International incidence of childhood brain and spinal tumours. Int J Epidemiol. 1994;23(3):458–464.
    1. Kaatsch P, Rickert CH, Kühl J, Schüz J, Michaelis J. Population-based epidemiologic data on brain tumors in German children. Cancer. 2001;92(12):3155–3164.
    1. Gnekow AK, Kortmann RD, Pietsch T, Emser A. Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy—report from the multicenter treatment study for children and adolescents with a low grade glioma—HIT-LGG 1996—of the Society of Pediatric Oncology and Hematology (GPOH). Klin Padiatr. 2004;216(6):331–342.
    1. Packer RJ, Ater J, Allen J, et al. . Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg. 1997;86(5):747–754.
    1. Laithier V, Grill J, Le Deley MC, et al. ; French Society of Pediatric Oncology Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy—results of the first French prospective study for the French Society of Pediatric Oncology. J Clin Oncol. 2003;21(24):4572–4578.
    1. Krishnatry R, Zhukova N, Guerreiro Stucklin AS, et al. . Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: a population-based study. Cancer. 2016;122(8):1261–1269.
    1. Gnekow AK, Falkenstein F, von Hornstein S, et al. . Long-term follow-up of the multicenter, multidisciplinary treatment study. Neuro Oncol. 2012;14(10):1265–1284.
    1. Bandopadhayay P, Bergthold G, London WB, et al. . Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer. 2014;61(7):1173–1179.
    1. Bartels U, Hawkins C, Jing M, et al. . Vascularity and angiogenesis as predictors of growth in optic pathway/hypothalamic gliomas. J Neurosurg. 2006;104(5 Suppl):314–320.
    1. Ribatti D, Guidolin D, Conconi MT, et al. . Vinblastine inhibits the angiogenic response induced by adrenomedullin in vitro and in vivo. Oncogene. 2003;22(41):6458–6461.
    1. Vacca A, Iurlaro M, Ribatti D, et al. . Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood. 1999;94(12):4143–4155.
    1. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 2002;62(13):3729–3735.
    1. Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 2001;15(15):1913–1925.
    1. Calzolari F, Malatesta P. Recent insights into PDGF-induced gliomagenesis. Brain Pathol. 2010;20(3):527–538.
    1. Geoerger B, Morland B, Ndiaye A, et al. ; Innovative Therapies for Children with Cancer European Consortium Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium. Eur J Cancer. 2009;45(13):2342–2351.
    1. Takei H, Yogeswaren ST, Wong KK, et al. . Expression of oligodendroglial differentiation markers in pilocytic astrocytomas identifies two clinical subsets and shows a significant correlation with proliferation index and progression free survival. J Neurooncol. 2008;86(2):183–190.
    1. Huang H, Colella S, Kurrer M, Yonekawa Y, Kleihues P, Ohgaki H. Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays. Cancer Res. 2000;60(24):6868–6874.
    1. Uutela M, Laurén J, Bergsten E, et al. . Chromosomal location, exon structure, and vascular expression patterns of the human PDGFC and PDGFD genes. Circulation. 2001;103(18):2242–2247.
    1. Yang I, Han SJ, Sughrue ME, Tihan T, Parsa AT. Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology. J Neurosurg. 2011;115(3):505–511.
    1. Simmons GW, Pong WW, Emnett RJ, et al. . Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol. 2011;70(1):51–62.
    1. Bajenaru ML, Garbow JR, Perry A, Hernandez MR, Gutmann DH. Natural history of neurofibromatosis 1-associated optic nerve glioma in mice. Ann Neurol. 2005;57(1):119–127.
    1. Badie B, Schartner JM. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery. 2000;46(4):957–961; discussion 961.
    1. Wallmann T, Zhang XM, Wallerius M, et al. . Microglia induce PDGFRB expression in glioma cells to enhance their migratory capacity. iScience. 2018;9:71–83.
    1. Tanaka H, Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res. 2009;69(17):6978–6986.
    1. Borg C, Terme M, Taïeb J, et al. . Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest. 2004;114(3):379–388.
    1. Kreutzman A, Porkka K, Mustjoki S. Immunomodulatory effects of tyrosine kinase inhibitors. Int Trends Immun. 2013;1(3):22–33.
    1. Vlahovic G, Ponce AM, Rabbani Z, et al. . Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts. Br J Cancer. 2007;97(6):735–740.
    1. Pietras K. Increasing tumor uptake of anticancer drugs with imatinib. Semin Oncol. 2004;31(2 Suppl 6):18–23.
    1. McLaughlin ME, Robson CD, Kieran MW, Jacks T, Pomeroy SL, Cameron S. Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): a case report and laboratory investigation. J Pediatr Hematol Oncol. 2003;25(8):644–648.
    1. Peyrl A, Azizi A, Czech T, et al. . Tumor stabilization under treatment with imatinib in progressive hypothalamic-chiasmatic glioma. Pediatr Blood Cancer. 2009;52(4):476–480.
    1. Manley PW, Drueckes P, Fendrich G, et al. . Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta. 2010;1804(3):445–453.
    1. Weisberg E, Manley PW, Breitenstein W, et al. . Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–141.
    1. Reinwald M, Schleyer E, Kiewe P, et al. . Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation. Biomed Res Int. 2014;2014:637059.
    1. Wayne AS, Macedo CR, Szczudlo T, Woodman RC. Nilotinib treatment in pediatric patients (pts) with Philadelphia chromosome-positive (Ph+) leukemia refractory to prior tyrosine kinase inhibitor (TKI) therapy: results from nilotinib compassionate use program. Blood. 2008;112(11):4264.
    1. Wang K, Ivanova A. Two-dimensional dose finding in discrete dose space. Biometrics. 2005;61(1):217–222.
    1. O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics. 1990;46(1):33–48.
    1. Doussau A, Asselain B, Le Deley MC, et al. . Dose-finding designs in pediatric phase I clinical trials: comparison by simulations in a realistic timeline framework. Contemp Clin Trials. 2012;33(4): 657–665.
    1. van den Bent MJ, Wefel JS, Schiff D, et al. . Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol. 2011;12(6): 583–593.
    1. Novartis Pharmaceuticals. Open label, phase ii study to evaluate efficacy and safety of oral nilotinib in Philadelphia positive (Ph+) chronic myelogenous leukemia (CML) pediatric patients. February 2019. . Accessed February 22, 2019.
    1. Heimbach T, Lin W, Hourcade-Potelleret F, et al. . Physiologically based pharmacokinetic modeling to supplement nilotinib pharmacokinetics and confirm dose selection in pediatric patients. J Pharm Sci. 2019;108(6):2191–2198.
    1. Lassaletta A, Scheinemann K, Zelcer SM, et al. . Phase II weekly vinblastine for chemotherapy-naïve children with progressive low-grade glioma: a Canadian pediatric brain tumor consortium study. J Clin Oncol. 2016;34(29):3537–3543.
    1. Singer JB, Shou Y, Giles F, et al. . UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia. 2007;21(11):2311–2315.
    1. Giles FJ, Yin OQ, Sallas WM, et al. . Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia. Eur J Clin Pharmacol. 2013;69(4):813–823.
    1. Bouffet E, Jakacki R, Goldman S, et al. . Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J Clin Oncol. 2012;30(12):1358–1363.
    1. Yuan Y, Yin G. Sequential continual reassessment method for two-dimensional dose finding. Stat Med. 2008;27(27):5664–5678.

Source: PubMed

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