Study for the Use of TKIs for Treatment of Cognitive Decline Due to Degenerative Dementias

Summary

The present study is designed as an open label study of patients with mild cognitive impairment or dementia to evaluate longer term tolerability and potential efficacy of tyrosine kinase inhibitors. Baseline and outcome measures in this study utilize validated tests that are appropriate for repeated measures which are not affected by practice effects. Advantages of this study include the fact that the neuropsychological testing instruments and advanced MRI imaging protocols that have been in routine clinical deployment provide for a high degree of availability and reliability for diagnosis and for monitoring change of status. Quality assurance is tightly controlled. The study population is sufficiently broad and the conditions of interest are sufficiently prevalent so that recruitment of the projected numbers of subjects is not a limiting factor. For a Phase I trial there is a proposed 150 patient sample to determine the frequency of common side effects in the population that is being studied. Subjects will be administered the initial dose of bosutinib, with dosage progressively increased over the course of the study. The initial dose of bosutinib is 100 mg tablet, once per day. The dose will be increased as tolerated up to 300 mg per day. All subjects will be started at 100 mg/day and the dose will be increased by 100 mg each month if the lower dose is tolerated without significant side effects. That is to say, the subject will take 100 mg/day every day for the first month, 200 mg/day every day for the second month, and 300 mg/day every day for the third month and for the remainder of the study, provided that adverse reactions do not prohibit continuation at this dosage. The investigators will be using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 to monitor, evaluate, and report adverse reactions on an ongoing basis. Stopping and dose reduction rules for reported adverse reactions have been taken from the package insert of bosutinib.

Timeline

Start

2016-09

Primary completion

2023-12-31

Completion

2025-12-31

Publications

• Background Carneiro BA, Kaplan JB, Giles FJ. Tyrosine kinase inhibitor therapy in chronic myeloid leukemia: update on key adverse events. Expert Rev Hematol. 2015 Aug;8(4):457-79. doi: 10.1586/17474086.2015.1041910. Epub 2015 May 4.
• Background Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Hum Mol Genet. 2013 Aug 15;22(16):3315-28. doi: 10.1093/hmg/ddt192. Epub 2013 May 10.
• Background Lonskaya I, Hebron M, Chen W, Schachter J, Moussa C. Tau deletion impairs intracellular beta-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models. Mol Neurodegener. 2014 Nov 10;9:46. doi: 10.1186/1750-1326-9-46.
• Background Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T. Cerebrospinal fluid beta-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol. 2009 Mar;66(3):382-9. doi: 10.1001/archneurol.2008.596.
• Background Targosz-Gajniak MG, Siuda JS, Wicher MM, Banasik TJ, Bujak MA, Augusciak-Duma AM, Opala G. Magnetic resonance spectroscopy as a predictor of conversion of mild cognitive impairment to dementia. J Neurol Sci. 2013 Dec 15;335(1-2):58-63. doi: 10.1016/j.jns.2013.08.023. Epub 2013 Aug 27.
• Background Hebron M, Moussa CE. Two sides of the same coin: tyrosine kinase inhibition in cancer and neurodegeneration. Neural Regen Res. 2015 Nov;10(11):1767-9. doi: 10.4103/1673-5374.165320. No abstract available.
• Background Lonskaya I, Hebron ML, Selby ST, Turner RS, Moussa CE. Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models. Neuroscience. 2015 Sep 24;304:316-27. doi: 10.1016/j.neuroscience.2015.07.070. Epub 2015 Jul 30.
• Background Hebron ML, Lonskaya I, Olopade P, Selby ST, Pagan F, Moussa CE. Tyrosine Kinase Inhibition Regulates Early Systemic Immune Changes and Modulates the Neuroimmune Response in alpha-Synucleinopathy. J Clin Cell Immunol. 2014 Sep 30;5:259. doi: 10.4172/2155-9899.1000259.
• Background Lonskaya I, Hebron ML, Desforges NM, Schachter JB, Moussa CE. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med (Berl). 2014 Apr;92(4):373-86. doi: 10.1007/s00109-013-1112-3. Epub 2013 Dec 13.
• Background Hebron ML, Lonskaya I, Moussa CE. Tyrosine kinase inhibition facilitates autophagic SNCA/alpha-synuclein clearance. Autophagy. 2013 Aug;9(8):1249-50. doi: 10.4161/auto.25368. Epub 2013 Jun 19.
• Background Lonskaya I, Hebron ML, Desforges NM, Franjie A, Moussa CE. Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med. 2013 Aug;5(8):1247-62. doi: 10.1002/emmm.201302771. Epub 2013 Jul 4.
• Background Folch J, Petrov D, Ettcheto M, Pedros I, Abad S, Beas-Zarate C, Lazarowski A, Marin M, Olloquequi J, Auladell C, Camins A. Masitinib for the treatment of mild to moderate Alzheimer's disease. Expert Rev Neurother. 2015 Jun;15(6):587-96. doi: 10.1586/14737175.2015.1045419. Epub 2015 May 11.
• Background Galvin JE. THE QUICK DEMENTIA RATING SYSTEM (QDRS): A RAPID DEMENTIA STAGING TOOL. Alzheimers Dement (Amst). 2015 Jun 1;1(2):249-259. doi: 10.1016/j.dadm.2015.03.003.
• Background Adamczuk K, Schaeverbeke J, Vanderstichele HM, Lilja J, Nelissen N, Van Laere K, Dupont P, Hilven K, Poesen K, Vandenberghe R. Diagnostic value of cerebrospinal fluid Abeta ratios in preclinical Alzheimer's disease. Alzheimers Res Ther. 2015 Dec 18;7(1):75. doi: 10.1186/s13195-015-0159-5.
• Background Llorens F, Schmitz M, Ferrer I, Zerr I. CSF biomarkers in neurodegenerative and vascular dementias. Prog Neurobiol. 2016 Mar-May;138-140:36-53. doi: 10.1016/j.pneurobio.2016.03.003. Epub 2016 Mar 22.
• Background Teipel SJ, Cavedo E, Grothe MJ, Lista S, Galluzzi S, Colliot O, Chupin M, Bakardjian H, Dormont D, Dubois B, Hampel H; Hippocampus Study Group. Predictors of cognitive decline and treatment response in a clinical trial on suspected prodromal Alzheimer's disease. Neuropharmacology. 2016 Sep;108:128-35. doi: 10.1016/j.neuropharm.2016.02.005. Epub 2016 Feb 10.
• Background Trebeschi S, Riederer I, Preibisch C, Bohn KP, Forster S, Alexopoulos P, Zimmer C, Kirschke JS, Valentinitsch A. Diagnostic Potential of Pulsed Arterial Spin Labeling in Alzheimer's Disease. Front Neurosci. 2016 Apr 19;10:154. doi: 10.3389/fnins.2016.00154. eCollection 2016.
• Background Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. doi: 10.1182/blood-2011-05-355594. Epub 2011 Aug 24.
• Background Jefferson AL, Beiser AS, Seshadri S, Wolf PA, Au R. APOE and mild cognitive impairment: the Framingham Heart Study. Age Ageing. 2015 Mar;44(2):307-11. doi: 10.1093/ageing/afu183. Epub 2014 Dec 11.
• Background Janofsky JS, McCarthy RJ, Folstein MF. The Hopkins Competency Assessment Test: a brief method for evaluating patients' capacity to give informed consent. Hosp Community Psychiatry. 1992 Feb;43(2):132-6. doi: 10.1176/ps.43.2.132.
• Background Appelbaum PS. Clinical practice. Assessment of patients' competence to consent to treatment. N Engl J Med. 2007 Nov 1;357(18):1834-40. doi: 10.1056/NEJMcp074045. No abstract available.

Drugs

Indications