Browsing by Author "Cudkowicz, Merit E."

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    Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study
    (Wolters Kluwer, 2022-01-25) Nowak, Richard J.; Coffey, Christopher S.; Goldstein, Jonathan M.; Dimachkie, Mazen M.; Benatar, Michael; Kissel, John T.; Wolfe, Gil I.; Burns, Ted M.; Freimer, Miriam L.; Nations, Sharon; Granit, Volkan; Smith, A. Gordon; Richman, David P.; Ciafaloni, Emma; Al-Lozi, Muhammad T.; Sams, Laura Ann; Quan, Dianna; Ubogu, Eroboghene; Pearson, Brenda; Sharma, Aditi; Yankey, Jon W.; Uribe, Liz; Shy, Michael; Amato, Anthony A.; Conwit, Robin; O'Connor, Kevin C.; Hafler, David A.; Cudkowicz, Merit E.; Barohn, Richard J.; NeuroNEXT NN103 BeatMG Study Team; Neurology, School of Medicine
    Objective: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). Methods: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. Results: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. Conclusions: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. Classification of evidence: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.
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    Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial
    (Oxford University Press, 2021-12-24) Griguer, Corinne E.; Oliva, Claudia R.; Coffey, Christopher S.; Cudkowicz, Merit E.; Conwit, Robin A.; Gudjonsdottir, Anna L.; Ecklund, Dixie J.; Fedler, Janel K.; Neill-Hudson, Tina M.; Nabors, Louis B.; Benge, Melanie; Hackney, James R.; Chase, Marianne; Leonard, Timothy P.; Patel, Toral; Colman, Howard; de la Fuente, Macarena; Chaudhary, Rekha; Marder, Karen; Kreisl, Teri; Mohile, Nimish; Chheda, Milan G.; McNeill, Katharine; Kumthekar, Priya; Dogan, Aclan; Drappatz, Jan; Puduvalli, Vinay; Kowalska, Agnes; Graber, Jerome; Gerstner, Elizabeth; Clark, Stephen; Salacz, Michael; Markert, James; Neurology, School of Medicine
    Background: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.