Abstract OT2-05-03: Does minocycline mitigate chemotherapy induced neuroinflammation? A phase II randomized placebo controlled study

Abstract

Background: Many breast cancer (BC) patients, particularly those who receive chemotherapy (chemo), experience affective symptoms and cognitive changes that can negatively impact their quality of life. Causal links between inflammatory mediators and the development of depressive-like behavior and cognitive defects, have been established in mouse models, including studies by our group showing increased microglial activation following chemo (A.C DeVries et al). Microglia are resident immune cells of the brain, which release proinflammatory cytokines when activated. Doxorubicin (DOX) induces microglial activation in the brain. Minocycline, a second generation tetracycline, has been shown to suppress inflammation by inhibiting microglial activation in CNS disease models. We hypothesize that (1) chemo activates microglia in the brains of women being treated for BC, which can precipitate or exacerbate depression, anxiety and cognitive deficits and (2) Minocycline administration during neoadjuvant or adjuvant chemo will prevent chemo-induced microglial activation and will reduce affective and cognitive symptom burden. Trial Design: This is a single center, Phase II, double blinded randomized study of minocycline (100 mg twice a day) vs placebo twice a day in women with BC receiving DOX-based or other chemo for BC. Pts will be randomized to either oral minocycline or placebo for up to a 1 week loading period plus chemo treatment period and an optional subsequent 2 week period. Eligibility Criteria: Women diagnosed with BC stages I-III initiating first line adjuvant or neoadjuvant chemo. Aims: (1) to evaluate symptoms related to anxiety and depression and cognitive changes during and after chemo completion (2) to evaluate markers of neuro inflammation as assessed by blood based inflammatory cytokines and central markers of inflammation and microglia activation using 1 F-Fludeoxyglucose and 11C-PK11195 positron emission tomography. Primary endpoints are changes in Center for Epidemiological Studies Depression Scale (CES-D) and State Trait Anxiety Index (STAI) from baseline to end of study after minocycline vs placebo intervention. Secondary endpoints are changes in cognitive function during chemo using validated cognitive testing including N-Back Test, Behavioural Rating Inventory of Executive Function (BRIEF) and the Multifactorial Memory Questionnaire Ability Scale (MMQ). Statistical Methods: Primary analysis for efficacy will be intention-to-treat. The main objective is to preliminarily evaluate the effect of minocycline on chemo-induced depressive symptoms in terms of changes in CES-D and STAI scores. Mixed models will be used to evaluate cognitive function changes. A sample size of 23 per group, will give 80% power to detect an effect size of 0.74 standard deviation (SD) difference between the 2 groups at significance level of 0.10 based on a 2 sided two-sample t-test. From our experience, attrition of less than 20% is expected for studies in this patient population in our center, and to account for this, we plan to recruit up to 60 patients. 16 of 46 evaluable pts have been accrued to date. Accrual started in January 2016. Funded by Pelotonia grant from The OSUCCC. Contact: Study PI: Maryam.lustberg@osumc.edu Citation Format: Boutrid H, Reinbolt R, Knopp M, Williams N, VanDeusen J, Sardesai S, Noonan A, Flora L, Gleich E, Pan X, Berger M, Vargo C, Wesolowski R, Ramaswamy B, DeVries AC, Lustberg M. Does minocycline mitigate chemotherapy induced neuroinflammation? A phase II randomized placebo controlled study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-05-03.

Minocycline in Treating Glioblastoma Multiforme: Far beyond a Conventional Antibiotic

“…A similar study has demonstrated that minocycline could prevent cerebral ischemia-induced neuroinflammation by the suppression of microglial activation [ 102 ]. Considering that minocycline suppresses inflammation by inhibiting microglial activation and cytokine production in CNS disease models [ 103 , 104 ], the anti-inflammatory effects of minocycline are ongoing in phase II randomized placebo-controlled study [ 105 ]. Clemens et al have shown that the anti-inflammatory effect of minocycline is via inhibition of local RA turnover in human microglial-like cells [ 92 ].…”