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CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL

BACKGROUND: Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing resu...

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Autores principales: Davi, Ruthanna, Majumdar, Antara, Bexon, Martin, Butowski, Nicholas, Chandhasin, Chandtip, Coello, Melissa, Das, Sunit, Merchant, Fahar, Merchant, Nina, Reardon, David, Roessner, Martin, Sampson, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453772/
http://dx.doi.org/10.1093/noajnl/vdab112.008
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author Davi, Ruthanna
Majumdar, Antara
Bexon, Martin
Butowski, Nicholas
Chandhasin, Chandtip
Coello, Melissa
Das, Sunit
Merchant, Fahar
Merchant, Nina
Reardon, David
Roessner, Martin
Sampson, John
author_facet Davi, Ruthanna
Majumdar, Antara
Bexon, Martin
Butowski, Nicholas
Chandhasin, Chandtip
Coello, Melissa
Das, Sunit
Merchant, Fahar
Merchant, Nina
Reardon, David
Roessner, Martin
Sampson, John
author_sort Davi, Ruthanna
collection PubMed
description BACKGROUND: Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial. METHODS: Using propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups. RESULTS: Through propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02). CONCLUSION: In advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control.
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spelling pubmed-84537722021-09-22 CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL Davi, Ruthanna Majumdar, Antara Bexon, Martin Butowski, Nicholas Chandhasin, Chandtip Coello, Melissa Das, Sunit Merchant, Fahar Merchant, Nina Reardon, David Roessner, Martin Sampson, John Neurooncol Adv Supplement Abstracts BACKGROUND: Drug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial. METHODS: Using propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups. RESULTS: Through propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02). CONCLUSION: In advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control. Oxford University Press 2021-09-21 /pmc/articles/PMC8453772/ http://dx.doi.org/10.1093/noajnl/vdab112.008 Text en © The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Supplement Abstracts
Davi, Ruthanna
Majumdar, Antara
Bexon, Martin
Butowski, Nicholas
Chandhasin, Chandtip
Coello, Melissa
Das, Sunit
Merchant, Fahar
Merchant, Nina
Reardon, David
Roessner, Martin
Sampson, John
CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL
title CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL
title_full CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL
title_fullStr CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL
title_full_unstemmed CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL
title_short CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL
title_sort clrm-09. incorporating external control arm in mdna55 recurrent glioblastoma registration trial
topic Supplement Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453772/
http://dx.doi.org/10.1093/noajnl/vdab112.008
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