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1. Predictive Probabilities Made Simple: A Fast and Accurate Method for Clinical Trial Decision Making

Author

Marion, Joe, Lorenzi, Liz, Allen-Savietta, Cora, Berry, Scott, and Viele, Kert

Subjects
Statistics - Applications
Abstract

Bayesian predictive probabilities are commonly used for interim monitoring of clinical trials through efficacy and futility stopping rules. Despite their usefulness, calculation of predictive probabilities, particularly in pre-experiment trial simulation, can be a significant challenge. We introduce an approximation for computing predictive probabilities using either a p-value or a posterior probability that significantly reduces this burden. We show the approximation has a high degree of concordance with standard Monte Carlo imputation methods for computing predictive probabilities, and present five simulation studies comparing the approximation to the full predictive probability for a range of primary analysis strategies: dichotomous, time-to-event, and ordinal endpoints, as well as historical borrowing and longitudinal modeling. We find that this faster method of predictive probability approximation works well in all five applications, thus significantly reducing the computational burden of trial simulation, allowing more virtual trials to be simulated to achieve greater precision in estimating trial operating characteristics., Comment: under review

Published
2024

2. Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Author

Meurer, William, Schmitzberger, Florian, Yeatts, Sharon, Ramakrishnan, Viswanathan, Abella, Benjamin, Aufderheide, Tom, Barsan, William, Benoit, Justin, Berry, Scott, Black, Joy, Bozeman, Nia, Broglio, Kristine, Brown, Jeremy, Brown, Kimberly, Carlozzi, Noelle, Caveney, Angela, Cho, Sung-Min, Chung-Esaki, Hangyul, Clevenger, Robert, Conwit, Robin, Cooper, Richelle, Crudo, Valentina, Daya, Mohamud, Harney, Deneil, Hsu, Cindy, Johnson, Nicholas, Khan, Imad, Khosla, Shaveta, Kline, Peyton, Kratz, Anna, Kudenchuk, Peter, Lewis, Roger, Madiyal, Chaitra, Meyer, Sara, Mosier, Jarrod, Mouammar, Marwan, Neth, Matthew, ONeil, Brian, Paxton, James, Perez, Sofia, Perman, Sarah, Sozener, Cemal, Speers, Mickie, Spiteri, Aimee, Stevenson, Valerie, Sunthankar, Kavita, Tonna, Joseph, Youngquist, Scott, Geocadin, Romergryko, and Silbergleit, Robert

Subjects
Bayesian adaptive trial, Cardiopulmonary Resuscitation, Hypothermia, Induced, Neuroprotection, Out-of-Hospital Cardiac Arrest, Humans, Hypothermia, Induced, Out-of-Hospital Cardiac Arrest, Coma, Time Factors, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Treatment Outcome, Recovery of Function, Neuroprotection, United States, Comparative Effectiveness Research
Abstract

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Published
2024

5. Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

Author

Albain, Kathy, Yau, Christina, Petricoin, Emanuel, Wolf, Denise, Lang, Julie, Chien, A, Haddad, Tufia, Forero-Torres, Andres, Wallace, Anne, Kaplan, Henry, Pusztai, Lajos, Euhus, David, Nanda, Rita, Elias, Anthony, Clark, Amy, Godellas, Constantine, Boughey, Judy, Isaacs, Claudine, Tripathy, Debu, Lu, Janice, Yung, Rachel, Gallagher, Rosa, Wulfkuhle, Julia, Brown-Swigart, Lamorna, Krings, Gregor, Chen, Yunn, Potter, David, Stringer-Reasor, Erica, Blair, Sarah, Asare, Smita, Wilson, Amy, Hirst, Gillian, Singhrao, Ruby, Buxton, Meredith, Clennell, Julia, Sanil, Ashish, Berry, Scott, Asare, Adam, Matthews, Jeffrey, DeMichele, Angela, Hylton, Nola, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope, Symmans, W, Vant Veer, Laura, Yee, Douglas, Berry, Donald, and Esserman, Laura

Subjects
Female, Humans, Antineoplastic Combined Chemotherapy Protocols, Bayes Theorem, Breast Neoplasms, Neoadjuvant Therapy, Paclitaxel, Receptor, ErbB-2, Receptor, TIE-2, Recombinant Fusion Proteins, Trastuzumab
Abstract

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy graduates if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Published
2024

6. Simvastatin in Critically Ill Patients with Covid-19.

Author

Hills, Thomas, Lorenzi, Elizabeth, Berry, Lindsay, Shyamsundar, Murali, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Aryal, Diptesh, Au, Carly, Beane, Abigail, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Burrell, Aidan, Buxton, Meredith, Calfee, Carolyn, Cecconi, Maurizio, Cheng, Allen, Cove, Matthew, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goligher, Ewan, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Harrison, David, Hashmi, Madiha, Higgins, Alisa, Huang, David, Ichihara, Nao, Jayakumar, Deva, Kruger, Peter, Lamontagne, François, Lampro, Lamprini, Lawler, Patrick, Marshall, John, Mason, Alexina, McGlothlin, Anna, McGuinness, Shay, McQuilten, Zoe, McVerry, Bryan, Mouncey, Paul, Murthy, Srinivas, Neal, Matthew, Nichol, Alistair, OKane, Cecilia, Parke, Rachael, Parker, Jane, Rabindrarajan, Ebenezer, Reyes, Luis, Rowan, Kathryn, Saito, Hiroki, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Shankar-Hari, Manu, Sinha, Pratik, Thompson, B, Turgeon, Alexis, Turner, Anne, van de Veerdonk, Frank, Weis, Sebastian, Young, Ian, Zarychanski, Ryan, McArthur, Colin, Angus, Derek, Berry, Scott, Derde, Lennie, Webb, Steve, Gordon, Anthony, McAuley, Daniel, and Lewis, Roger

Subjects
Humans, Bayes Theorem, COVID-19, COVID-19 Drug Treatment, Critical Illness, Hospital Mortality, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Treatment Outcome
Abstract

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was

Published
2023

7. Wastewater Surveillance for Identifying SARS-CoV-2 Infections in Long-Term Care Facilities, Kentucky, USA, 2021-2022

Author

Keck, James W., Adatorwovor, Reuben, Liversedge, Matthew, Mijotavich, Blazan, Olsson, Cullen, Strike, William D., Amirsoleimani, Atena, Noble, Ann, Torabi, Soroosh, Rockward, Alexus, Banadaki, Mohammad Dehghan, Smith, Ted, Lacy, Parker, and Berry, Scott M.

Subjects
Kentucky -- Health aspects, Epidemics -- Risk factors -- United States, Wastewater -- Health aspects, Sentinel health events -- Methods, Water sampling -- Methods, Long-term care facilities -- Health aspects, Health
Abstract

Persons living in long-term care facilities (LTCFs) have experienced disproportionate illnesses and deaths from the COVID-19 pandemic. By June 2020, >50,000 COVID-19 deaths had occurred in LTCF residents in the [...]

Published
2024
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8. Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest

Author

Meurer, William J., Schmitzberger, Florian F., Yeatts, Sharon, Ramakrishnan, Viswanathan, Abella, Benjamin, Aufderheide, Tom, Barsan, William, Benoit, Justin, Berry, Scott, Black, Joy, Bozeman, Nia, Broglio, Kristine, Brown, Jeremy, Brown, Kimberly, Carlozzi, Noelle, Caveney, Angela, Cho, Sung-Min, Chung-Esaki, Hangyul, Clevenger, Robert, Conwit, Robin, Cooper, Richelle, Crudo, Valentina, Daya, Mohamud, Harney, Deneil, Hsu, Cindy, Johnson, Nicholas J., Khan, Imad, Khosla, Shaveta, Kline, Peyton, Kratz, Anna, Kudenchuk, Peter, Lewis, Roger J., Madiyal, Chaitra, Meyer, Sara, Mosier, Jarrod, Mouammar, Marwan, Neth, Matthew, O’Neil, Brian, Paxton, James, Perez, Sofia, Perman, Sarah, Sozener, Cemal, Speers, Mickie, Spiteri, Aimee, Stevenson, Valerie, Sunthankar, Kavita, Tonna, Joseph, Youngquist, Scott, Geocadin, Romergryko, and Silbergleit, Robert

Published
2024
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9. A randomized, embedded, pragmatic, Bayesian clinical trial examining clinical decision support for high flow nasal cannula management in children with bronchiolitis: design and statistical analysis plan

Author

Horvat, Christopher M., Suresh, Srinivasan, James, Nathan, Aneja, Rajesh K., Au, Alicia K., Berry, Scott, Blumer, Arthur, Bricker, Kelly, Clark, Robert S. B., Dolinich, Heidilyn, Hahner, Sheila, Jockel, Christina, Kalivoda, Jordan, Loar, India, Marasco, Denee, Marcinick, Adrienne, Marroquin, Oscar, O’brien, Jonathan, Pelletier, Jonathan, Ramgopal, Sriram, Venkataraman, Shekhar, Angus, Derek C., and Butler, Gabriella

Published
2024
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11. Use of Non-concurrent Common Control in Master Protocols in Oncology Trials: Report of an American Statistical Association Biopharmaceutical Section Open Forum Discussion

Author

Sridhara, Rajeshwari, Marchenko, Olga, Jiang, Qi, Pazdur, Richard, Posch, Martin, Berry, Scott, Theoret, Marc, Shen, Yuan Li, Gwise, Thomas, Hess, Lorenzo, Raven, Andrew, Rantell, Khadija, Roes, Kit, Simon, Richard, Redman, Mary, Ji, Yuan, and Lu, Cindy

Subjects
Statistics - Applications, 62P10
Abstract

This article summarizes the discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum that took place on December 10, 2020 and was organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group, in coordination with the US FDA Oncology Center of Excellence. Diverse stakeholders including experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on the use of non-concurrent control in Master Protocols for oncology trials. While the use of non-concurrent control with the concurrent control may increase the power of detecting the therapeutic difference between a treatment and the control, the panelists had diverse opinion on the statistical approaches for modeling non-concurrent and concurrent controls. Some were more concerned about the temporality of the non-concurrent control and bias introduced by different confounders related to time, e.g., changes in standard of care, changes in patient population, changes in recruiting strategies, changes in assessment of endpoints. Nevertheless, in some situations such as when the recruitment is extremely challenging for a rare disease, the panelists concluded that the use of a non-concurrent control can be justified.

Published
2022
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12. Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

Author

Lang, Julie E, Forero-Torres, Andres, Yee, Douglas, Yau, Christina, Wolf, Denise, Park, John, Parker, Barbara A, Chien, A Jo, Wallace, Anne M, Murthy, Rashmi, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Yung, Rachel L, Isaacs, Claudine, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Stringer-Reasor, Erica, Price, Elissa, Joe, Bonnie, Liu, Minetta C, Brown-Swigart, Lamorna, Petricoin, Emanuel F, Wulfkuhle, Julia D, Buxton, Meredith, Clennell, Julia L, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Symmans, W Fraser, van 't Veer, Laura J, Hylton, Nola M, DeMichele, Angela M, Berry, Donald A, and Esserman, Laura J

Subjects
Clinical Research, Clinical Trials and Supportive Activities, Prevention, Breast Cancer, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions
Abstract

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379.

Published
2022

17. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial.

Author

Clark, Amy S, Yau, Christina, Wolf, Denise M, Petricoin, Emanuel F, van 't Veer, Laura J, Yee, Douglas, Moulder, Stacy L, Wallace, Anne M, Chien, A Jo, Isaacs, Claudine, Boughey, Judy C, Albain, Kathy S, Kemmer, Kathleen, Haley, Barbara B, Han, Hyo S, Forero-Torres, Andres, Elias, Anthony, Lang, Julie E, Ellis, Erin D, Yung, Rachel, Tripathy, Debu, Nanda, Rita, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Gallagher, Rosa I, Helsten, Teresa, Roesch, Erin, Ewing, Cheryl A, Alvarado, Michael, Crane, Erin P, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Steeg, Katherine, Asare, Adam, Matthews, Jeffrey B, Berry, Scott, Sanil, Ashish, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Schwab, Richard B, Symmans, W Fraser, Hylton, Nola M, Berry, Donald A, Esserman, Laura J, and DeMichele, Angela M

Subjects
Humans, Breast Neoplasms, Paclitaxel, Maytansine, Receptor, erbB-2, Neoadjuvant Therapy, Adult, Aged, Middle Aged, Antibodies, Monoclonal, Humanized, Biomarkers, Tumor, Trastuzumab, Ado-Trastuzumab Emtansine, Receptor, ErbB-2, Clinical Trials and Supportive Activities, Clinical Research, Breast Cancer, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals
Abstract

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Published
2021

18. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

Author

Yee, Douglas, Isaacs, Claudine, Wolf, Denise M, Yau, Christina, Haluska, Paul, Giridhar, Karthik V, Forero-Torres, Andres, Jo Chien, A, Wallace, Anne M, Pusztai, Lajos, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Kemmer, Kathleen, Yung, Rachel L, Pohlmann, Paula R, Tripathy, Debu, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Petricoin, Emanuel F, Stringer-Reasor, Erica, Falkson, Carla I, Majure, Melanie, Mukhtar, Rita A, Helsten, Teresa L, Moulder, Stacy L, Robinson, Patricia A, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Hylton, Nola M, DeMichele, Angela, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Fraser Symmans, W, Van't Veer, Laura J, Berry, Donald A, and Esserman, Laura J

Subjects
Diabetes, Cancer, Breast Cancer, 6.1 Pharmaceuticals
Abstract

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Published
2021

20. Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Author

Sánchez-Montalva, Adrian, Estevez, Ana Belén, Sánchez, Àlex, Sanjuan, Anna, Sena, Elena, Granados, Emma, Arévalo de Andrés, Esther, Nuñez, Fátima, Arteaga, Gara, Fuentes Ruiz, Gabriela Perez, Fernández, Guillermo, Rivera-Esteban, Jesus, Comella, Joan, Ramos-Quiroga, Josep Antoni, Genescà, Joan, Espinosa, Juan, Pericàs, Juan Manuel, Murcia, Lada, Cash-Gibson, Lucinda, de Valles Silvosa, Maria, Barroso de Sousa, María Fernanda, Sánchez-Maroto Carrizo, Olga, Ibañez-Jiménez, Pol, Augustin, Salvador, Perez-Hoyos, Santiago, Rodríguez-Navarro, Sarai, Muñoz-Martínez, Sergio, Serres, Silvia, Kalko, Susana, Michon, Amelie, Ussi, Anton, Lydall, Ben, van de Ketterij, Edwin, Quiles, Ignacio, Carapina, Tamara, Kumaus, Constantin, Ramazanova, Dariga, Meyer, Elias Laurin, Koenig, Franz, Roig, Marta Bofill, Brunner, Martin, Posch, Martin, Krotka, Pavla, Zehetmayer, Sonja, Carton, Charlotte, Legius, Eric, Begum, Amina, Pariante, Carmine, Worrell, Courtney, Lombardo, Giulia, Sforzini, Luca, Brown, Mollie, Gullet, Nancy, Amasi-Hartoonian, Nare, Ferner, Rosalie, Kose, Melisa, Spitaleri, Andrea, Ghodousi, Arash, Di Serio, Clelia, Cirillo, Daniela, Cugnata, Federica, Saluzzo, Francesca, Benedetti, Francesco, Scarale, Maria Giovanna, Zini, Michela, Rancoita, Paola Maria, Alagna, Riccardo, Poletti, Sara, Dhaenens, Britt, Van Der Lei, Johan, de Steenwinkel, Jurriaan, Moinat, Maxim, Oostenbrink, Rianne, Hoogendijk, Witte, Hölscher, Michael, Heinrich, Norbert, Otte, Christian, Potratz, Cornelia, Zocholl, Dario, Kulakova, Eugenia, Tacke, Frank, Brasanac, Jelena, Leubner, Jonas, Krajewska, Maja, Freitag, Michaela Maria, Gold, Stefan, Zoller, Thomas, Chae, Woo Ri, Daniel, Christel, Kara, Leila, Vaterkowski, Morgan, Griffon, Nicolas, Wolkenstein, Pierre, Pais, Raluca, Ratziu, Vlad, Voets, David, Maes, Christophe, Kalra, Dipak, Thienpoint, Geert, Deckerck, Jens, Lea, Nathan, Singleton, Peter, Viele, Kert, Jacko, Peter, Berry, Scott, Parke, Tom, Aydin, Burç, Kubiak, Christine, Demotes, Jacques, Ueda, Keiko, Matei, Mihaela, Contrino, Sergio, Röhl, Claas, Cordero, Estefania, Greenhalgh, Fiona, Jarke, Hannes, Angelova, Juliana, Boudes, Mathieu, Dressler, Stephan, Strammiello, Valentina, Anstee, Quentin, Gutierrez-Ibarluzea, Iñaki, Otte, Maximilian, Heimbach, Natalie, Hofner, Benjamin, Burgwinkel, Cora, Kaestel, Hue, Hees, Katharina, Nguyen, Quynh, Prieto-Alhambra, Daniel, Tan, Eng Hooi (Cheryl), Raviglione, Mario, de Colombani, Pierpaolo, Villa, Simone, Maron, Eduard, Evans, Gareth, Savitz, Adam J., Van Dessel, Ann, Duca, Anna, Kaminski, Anne, Wouters, Bie, Porter, Brandon, Charron, Catherine, Spiertz, Cecile, Zizzamia, Christopher, Millar, Daniel, Hasselbaink, Danny, Orr, David, Kesters, Divya, Hubin, Ellen, Davies, Emma, Didden, Eva-Maria, Guz, Gabriela, Verstraete, Evelyn, Mao, Gary, Capuano, George, Martynowicz, Heddie, De Smedt, Heidi, Larsson, Ingela, Bruegelmans, Ines, Coste, Isabelle, Gonzalez Moreno, Jesus Maria, Niewczas, Julia, Xu, Jiajun, Rombouts, Karin, Woo, Katherine, Wuyts, Kathleen, Hersh, Kathryn, Oldenburg, Khrista, Zhang, Lingjiao, Schmidt, Mark, Szuch, Mark, Todorovic, Marija, Mangelaars, Maartje, Grewal, Melissa, Sandor, Molli, Di Prospero, Nick, Van Houten, Pamela, Minnick, Pansy, Bastos, Polyana, Patrizi, Robert, Morello, Salvatore, De Wilde, Severijn, Sun, Tao, Kline, Timothy, de Marez, Tine, Mielke, Tobias, Reijns, Tom, Popova, Vanina, Flossbach, Yanina, Tymofyeyev, Yevgen, De Groote, Zeger, Sverdlov, Alex, Bobirca, Alexandra, Krause, Annekatrin, Bobrica, Catalin, Heintz, Daniela, Magirr, Dominic, Glimm, Ekkehard, Baffert, Fabienne, Castiglione, Federica, Caruso, Franca, Patalano, Francesco, Bretz, Frank, Heimann, Guenter, Carbarns, Ian, Rodríguez, Ignacio, Ratescu, Ioana, Hampson, Lisa, Pedrosa, Marcos, Hark, Mareile, Mesenbrink, Peter, Penna, Sabina Hernandez, Bergues-Lang, Sarah, Baltes-Engler, Susanne, Arsiwala, Tasneem, Mondragon, Valeria Jordan, Guo, Hua, Da Costa, Jose Leite, Burman, Carl-Fredrik, Kirk, George, Aaes-Jørgensen, Anders, Dirach, Jorgen, Kjær, Mette Skalshøi, Martin, Alexandra, Hristov, Diyan, Rousseaux, Florent, Hittel, Norbert, Dornheim, Robert, Evans, Daniel, Sykes, Nick, Couvert, Camille, Leuven, Catherine, Notelet, Loïc, Gidh-Jain, Madhavi, Jouannin, Mathieu, Ammour, Nadir, Pierre, Suzanne, Haufe, Volker, Dong, Yingwen, Dubanchet, Catherine, de Préville, Nathalie, Baltauss, Tania, Jian, Zhu, Shnider, Sara, Bar-El, Tal, Bakker, Annette, Nievo, Marco, Iloeje, Uche, Conradie, Almari, Auffarrth, Ece, Lombard, Leandra, Benhayoun, Majda, Olugbosi, Morounfolu, Seidel, Stephanie S., Gumí, Berta, Guzmán, Claudia García, Molero, Eva, Pairó, Gisela, Machin, Núria, Cardelús, Raimon, Ramasastry, Saira, Pelzer, Saskia, Kremer, Andreas, Lindfors, Erno, Lynch, Chris, Spiertz, Cécile, Machín, Núria, and Pericàs, Juan M.

Published
2024
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21. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, and Krishnan, Vidya

Subjects
Cardiovascular, Clinical Trials and Supportive Activities, Clinical Research, Hematology, Transplantation, Good Health and Well Being, Adult, Aged, Anticoagulants, COVID-19, Female, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Hospital Mortality, Humans, Male, Middle Aged, Survival Analysis, Thrombosis, COVID-19 Drug Treatment, ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Published
2021

22. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

Author

ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, and King, Andrew J

Subjects
ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Humans, Thrombosis, Hemorrhage, Heparin, Heparin, Low-Molecular-Weight, Anticoagulants, Hospital Mortality, Survival Analysis, Adult, Aged, Middle Aged, Female, Male, COVID-19, Hematology, Clinical Trials and Supportive Activities, Transplantation, Clinical Research, Cardiovascular, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

Published
2021

23. Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

Author

Arabi, Yaseen M, Gordon, Anthony C, Derde, Lennie PG, Nichol, Alistair D, Murthy, Srinivas, Beidh, Farah Al, Annane, Djillali, Swaidan, Lolowa Al, Beane, Abi, Beasley, Richard, Berry, Lindsay R, Bhimani, Zahra, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, De Jong, Menno, Detry, Michelle A, Duffy, Eamon J, Estcourt, Lise J, Fitzgerald, Mark, Fowler, Rob, Girard, Timothy D, Goligher, Ewan C, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa M, Hills, Thomas E, Horvat, Christopher M, Huang, David T, King, Andrew J, Lamontagne, Francois, Lawler, Patrick R, Lewis, Roger, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Malakouti, Salim, McAuley, Daniel F, McGlothlin, Anna, Mcguinness, Shay, McVerry, Bryan J, Montgomery, Stephanie K, Morpeth, Susan C, Mouncey, Paul R, Orr, Katrina, Parke, Rachael, Parker, Jane C, Patanwala, Asad E, Rowan, Kathryn M, Santos, Marlene S, Saunders, Christina T, Seymour, Christopher W, Shankar-Hari, Manu, Tong, Steven YC, Turgeon, Alexis F, Turner, Anne M, Van de Veerdonk, Frank Leo, Zarychanski, Ryan, Green, Cameron, Berry, Scott, Marshall, John C, McArthur, Colin, Angus, Derek C, and Webb, Steven A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Comparative Effectiveness Research, Clinical Research, Clinical Trials and Supportive Activities, Good Health and Well Being, Adult, Antiviral Agents, Bayes Theorem, Critical Illness, Drug Combinations, Humans, Hydroxychloroquine, Lopinavir, Ritonavir, SARS-CoV-2, COVID-19 Drug Treatment, Adaptive platform trial, Intensive care, Pneumonia, Pandemic, COVID-19, Lopinavir-ritonavir, REMAP-CAP Investigators, Public Health and Health Services, Emergency & Critical Care Medicine, Clinical sciences
Abstract

PurposeTo study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).MethodsCritically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.ResultsWe randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).ConclusionAmong critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

Published
2021

24. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial.

Author

Pusztai, Lajos, Yau, Christina, Han, Hyo, Du, Lili, Wallace, Anne, String-Reasor, Erica, Boughey, Judy, Chien, A, Elias, Anthony, Beckwith, Heather, Nanda, Rita, Albain, Kathy, Clark, Amy, Kemmer, Kathleen, Kalinsky, Kevin, Isaacs, Claudine, Thomas, Alexandra, Helsten, Theresa, Forero-Torres, Andres, Liu, Minetta, Brown-Swigart, Lamorna, Petricoin, Emmanuel, Wulfkuhle, Julia, Asare, Smita, Wilson, Amy, Singhrao, Ruby, Sit, Laura, Berry, Scott, Sanil, Ashish, Asare, Adam, Matthews, Jeffrey, Perlmutter, Jane, Melisko, Michelle, Rugo, Hope, Schwab, Richard, Symmans, W, Yee, Doug, Vant Veer, Laura, DeMichele, Angela, Berry, Donald, Esserman, Laura, Hylton, Nola, Wolf, Denise, Shatsky, Rebecca, and Hirst, Gillian

Subjects
DNA repair inhibitor, breast cancer, clinical trial, immunotherapy, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Female, Follow-Up Studies, Humans, Middle Aged, Neoadjuvant Therapy, Paclitaxel, Phthalazines, Piperazines, Prognosis, Receptor, ErbB-2, Survival Rate, Young Adult
Abstract

The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.

Published
2021

25. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

Author

Gordon, Anthony, Mouncey, Paul, Al-Beidh, Farah, Rowan, Kathryn, Nichol, Alistair, Arabi, Yaseen, Annane, Djillali, Beane, Abi, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buzgau, Adrian, Cheng, Allen, Detry, Michelle, Duffy, Eamon, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Haniffa, Rashan, Higgins, Alisa, Hills, Thomas, Horvat, Christopher, Lamontagne, Francois, Lawler, Patrick, Leavis, Helen, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mayr, Florian, McAuley, Daniel, McGlothlin, Anna, McGuinness, Shay, McVerry, Bryan, Montgomery, Stephanie, Morpeth, Susan, Murthy, Srinivas, Orr, Katrina, Parke, Rachael, Parker, Jane, Patanwala, Asad, Pettilä, Ville, Rademaker, Emma, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Shankar-Hari, Manu, Sligl, Wendy, Turgeon, Alexis, Turner, Anne, van de Veerdonk, Frank, Zarychanski, Ryan, Green, Cameron, Lewis, Roger, Angus, Derek, McArthur, Colin, Berry, Scott, Webb, Steve, and Derde, Lennie

Subjects
Adult, Aged, Antibodies, Monoclonal, Humanized, COVID-19, Critical Illness, Female, Hospital Mortality, Humans, Intensive Care Units, Male, Middle Aged, Odds Ratio, Receptors, Interleukin-6, Respiration, Artificial, COVID-19 Drug Treatment
Abstract

BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Published
2021

26. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

Author

Mendez, Guillermo, O'Connor, Juan Manuel, Yanzi Castilla, Alvaro, Cundom, Juan, Kaen, Diego, Wong, Rachel, Ng, Weng, Aghmesheh, Morteza, Peressoni, Mauricio, Andrade, Carlos, Franke, Fabio, Alves, Gustavo, Cruz, Felipe Jose, Vianna, Karina, Monteiro, Maria Marcela, Raphael, Michael, Berry, Scott, Jang, Raymond, Tan, Ann, Asselah, Jamil, Yanez Weber, Patricio, Mahave, Mauricio, Sanchez, Cesar, Salman, Pamela, Bai, Yuxian, Li, Jin, Zhang, Xiaochun, Liu, Tianshu, Lin, Xiaoyan, Qin, Shukui, Yang, Jianwei, Luo, Suxia, Li, Wei, Ying, Jieer, Chen, Xi, Zeng, Shan, Qu, Yanli, Yang, Lin, Zhao, Lin, Chen, Ping, Pan, Hongming, Li, Enxiao, Ye, Feng, Lu, Jianwei, Liang, Xinjun, Zhao, Qun, Yin, Xianli, Li, Junhe, Ling, Yang, Lv, Guoqing, Li, Shouguo, Guerrero, Alvaro, Rubiano, Juan, Gonzalez Fernandez, Manuel, Manneh Kopp, Ray, Guzman Ramirez, Adrian, Corrales, Luis, Gonzalez Herrera, Ileana, Melichar, Bohuslav, Buchler, Tomas, Svoboda, Tomas, Obermannova, Radka, Vrana, David, Cvek, Jakub, Pfeiffer, Per, Baeksgaard, Lene, Yilmaz, Mette, Boige, Valerie, Lopez-Trabada, Daniel, Borg, Christophe, Pannier, Diane, Hiret, Sandrine, Di Fiore, Frederic, Metges, Jean-Philippe, Arnold, Dirk, Martens, Uwe, Lordick, Florian, Stein, Alexander, Castro, Hugo, Lopez, Karla, Ramirez, Julio, Aguilar, Mynor, Chivalan, Marco, Chan, Wendy, Cheng, Ashley, Yeo, Winnie, Arkosy, Peter, Csoszi, Tibor, Hitre, Erika, Horvath, Zsolt, Lowery, Maeve, McDermott, Ray, Morris, Patrick, Hubert, Ayala, Brenner, Baruch, Ben-Aharon, Irit, Shacham-Shmueli, Einat, Man, Sofia, Pelles Avraham, Sharon, Brenner, Ronen, Mishaeli, Moshe, Di Bartolomeo, Maria, Fazio, Nicola, Lonardi, Sara, Garufi, Carlo, Satoh, Taroh, Hara, Hiroki, Iwagami, Shiro, Yasui, Hisateru, Tsuda, Masahiro, Shimoyama, Tatsu, Shoji, Hirokazu, Sugimoto, Naotoshi, Shibata, Nobuhiro, Yamaguchi, Kensei, Amagai, Kenji, Choda, Yasuhiro, Esaki, Taito, Yabusaki, Hiroshi, Oshima, Takashi, Tsuji, Akihito, Kawakami, Hisato, Kawazoe, Akihito, Ishido, Kenji, Kadowaki, Shigenori, Martinez Rodriguez, Jorge, Herrera Martinez, Marytere, Huitzil Melendez, Fidel, Ramirez Godinez, Francisco, Balancan, Paola, Damianovich, Dragan, Castro Oliden, Victor, Grados, Julio, Torres, Cesar, Wyrwicz, Lucjan, Wysocki, Piotr, Hajac, Lukasz, Zolnierek, Jakub, Karaszewska, Boguslawa, Rha, Sun Young, Lee, Jeeyun, Ryu, Min-Hee, Oh, Do-Youn, Orlova, Rashida, Tjulandin, Sergey, Fadeeva, Natalia, Makarycheva, Yulia, Nosov, Dmitry, Smagina, Maria, Chan, Sze, Jacobs, Conrad, Kraus, Peter, Landers, Gregory, Robertson, Barbara, Ruff, Paul, Schoeman, Elizabeth, Maurel, Jean-Marc, Diez Garcia, Marc, Jimenez Fonseca, Paula, Gallego Plazas, Javier, Rivera Herrero, Fernando, Miranda Poma, Jesus, Layos Romero, Laura, Fritsch, Ralph, Bastian, Sara, Winterhalder, Ralph, Dosso, Sara De, Kossler, Thibaud, Yeh, Kun-Huei, Yen, Chia-Jui, Chen, Yen-Yang, Lin, Johnson, Bilici, Mehmet, Ozguroglu, Mustafa, Cil, Timucin, Oksuzoglu, Berna, Harputluoglu, Hakan, Karaoglu, Aziz, Hacibekiroglu, Ilhan, Erdogan, Bulent, Yalcin, Suayib, Adamchuk, Hryhoriy, Bondarenko, Igor, Kolesnik, Oleksii, Ostapenko, Yuriy, Kryzhanivska, Anna, Leshchenko, Lurii, Ilin, Ievgen, Shparyk, Yaroslav, Trukhin, Dmytro, Voitko, Nataliia, Roy, Rajarshi, Young, Anna-Mary, Medley, Louise, Shiu, Kai-Keen, Celano, Paul, Overton, Lindsay, Raj, Moses, Dunne, Richard, Wainberg, Zev, Dayyani, Farshid, Larson, Timothy, Kochenderfer, Mark, Yañez, Patricio, Rivera, Fernando, Alves, Gustavo Vasconcelos, Garrido, Marcelo, Fernández, Manuel González, Lowery, Maeve A, Çil, Timuçin, Cruz, Felipe Melo, Wainberg, Zev A, Yin, Lina, Bordia, Sonal, Bhagia, Pooja, and Wyrwicz, Lucjan S

Published
2023
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30. A minimal common outcome measure set for COVID-19 clinical research

Author

infection, WHO Working Group on the Clinical Characterisation and Management of COVID-19, Marshall, John C, Murthy, Srinivas, Diaz, Janet, Adhikari, NK, Angus, Derek C, Arabi, Yaseen M, Baillie, Kenneth, Bauer, Michael, Berry, Scott, Blackwood, Bronagh, Bonten, Marc, Bozza, Fernando, Brunkhorst, Frank, Cheng, Allen, Clarke, Mike, Dat, Vu Quoc, de Jong, Menno, Denholm, Justin, Derde, Lennie, Dunning, Jake, Feng, Xiaobin, Fletcher, Tom, Foster, Nadine, Fowler, Rob, Gobat, Nina, Gomersall, Charles, Gordon, Anthony, Glueck, Thomas, Harhay, Michael, Hodgson, Carol, Horby, Peter, Kim, YaeJean, Kojan, Richard, Kumar, Bharath, Laffey, John, Malvey, Denis, Martin-Loeches, Ignacio, McArthur, Colin, McAuley, Danny, McBride, Stephen, McGuinness, Shay, Merson, Laura, Morpeth, Susan, Needham, Dale, Netea, Mihai, Oh, Myoung-Don, Phyu, Sabai, Piva, Simone, Qiu, Ruijin, Salisu-Kabara, Halima, Shi, Lei, Shimizu, Naoki, Sinclair, Jorge, Tong, Steven, Turgeon, Alexis, Uyeki, Tim, van de Veerdonk, Frank, Webb, Steve, Williamson, Paula, Wolf, Timo, and Zhang, Junhua

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Infectious Diseases, Infection, Good Health and Well Being, Betacoronavirus, COVID-19, Clinical Trials as Topic, Coronavirus Infections, Humans, Outcome Assessment, Health Care, Pandemics, Patient Outcome Assessment, Pneumonia, Viral, SARS-CoV-2, Survival Analysis, Treatment Outcome, Viral Load, WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection, Medical Microbiology, Public Health and Health Services, Microbiology, Clinical sciences, Medical microbiology, Epidemiology
Abstract

Clinical research is necessary for an effective response to an emerging infectious disease outbreak. However, research efforts are often hastily organised and done using various research tools, with the result that pooling data across studies is challenging. In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium have developed a minimum set of common outcome measures for studies of COVID-19. This set includes three elements: a measure of viral burden (quantitative PCR or cycle threshold), a measure of patient survival (mortality at hospital discharge or at 60 days), and a measure of patient progression through the health-care system by use of the WHO Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness. We urge investigators to include these key data elements in ongoing and future studies to expedite the pooling of data during this immediate threat, and to hone a tool for future needs.

Published
2020

31. The Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) Study: Rationale and Design

Author

Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Subjects
Influenza, Cancer, Clinical Research, Lung, Clinical Trials and Supportive Activities, Vaccine Related, Pneumonia & Influenza, Comparative Effectiveness Research, Patient Safety, Infectious Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Anti-Bacterial Agents, Antiviral Agents, Betacoronavirus, COVID-19, Community-Acquired Infections, Coronavirus Infections, Evidence-Based Medicine, Humans, Influenza, Human, Pandemics, Pneumonia, Pneumonia, Viral, Point-of-Care Systems, SARS-CoV-2, randomized clinical trial, Bayesian adaptive platform trial, master protocol, community-acquired pneumonia, coronavirus disease 2019, Bayesian adaptive, platform trial
Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Published
2020

32. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.

Author

Angus, Derek C, Berry, Scott, Lewis, Roger J, Al-Beidh, Farah, Arabi, Yaseen, van Bentum-Puijk, Wilma, Bhimani, Zahra, Bonten, Marc, Broglio, Kristine, Brunkhorst, Frank, Cheng, Allen C, Chiche, Jean-Daniel, De Jong, Menno, Detry, Michelle, Goossens, Herman, Gordon, Anthony, Green, Cameron, Higgins, Alisa M, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Litton, Edward, Marshall, John, McGlothlin, Anna, McGuinness, Shay, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, O'Neill, Genevieve K, Parke, Rachael, Parker, Jane, Rohde, Gernot, Rowan, Kathryn, Turner, Anne, Young, Paul, Derde, Lennie, McArthur, Colin, and Webb, Steven A

Subjects
Humans, Community-Acquired Infections, Pneumonia, Viral, Coronavirus Infections, Pneumonia, Anti-Bacterial Agents, Antiviral Agents, Evidence-Based Medicine, Point-of-Care Systems, Influenza, Human, Pandemics, Betacoronavirus, COVID-19, SARS-CoV-2, Bayesian adaptive, community-acquired pneumonia, coronavirus disease 2019, master protocol, platform trial, randomized clinical trial, Bayesian adaptive platform trial, Respiratory System, Clinical Sciences
Abstract

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Published
2020

33. MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

Author

Chien, A Jo, Tripathy, Debasish, Albain, Kathy S, Symmans, W Fraser, Rugo, Hope S, Melisko, Michelle E, Wallace, Anne M, Schwab, Richard, Helsten, Teresa, Forero-Torres, Andres, Stringer-Reasor, Erica, Ellis, Erin D, Kaplan, Henry G, Nanda, Rita, Jaskowiak, Nora, Murthy, Rashmi, Godellas, Constantine, Boughey, Judy C, Elias, Anthony D, Haley, Barbara B, Kemmer, Kathleen, Isaacs, Claudine, Clark, Amy S, Lang, Julie E, Lu, Janice, Korde, Larissa, Edmiston, Kirsten K, Northfelt, Donald W, Viscusi, Rebecca K, Yee, Douglas, Perlmutter, Jane, Hylton, Nola M, Van't Veer, Laura J, DeMichele, Angela, Wilson, Amy, Peterson, Garry, Buxton, Meredith B, Paoloni, Melissa, Clennell, Julia, Berry, Scott, Matthews, Jeffrey B, Steeg, Katherine, Singhrao, Ruby, Hirst, Gillian L, Sanil, Ashish, Yau, Christina, Asare, Smita M, Berry, Donald A, and Esserman, Laura J

Subjects
Clinical Research, Clinical Trials and Supportive Activities, Cancer, Prevention, Breast Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Doxorubicin, Female, Heterocyclic Compounds, 3-Ring, Humans, Middle Aged, Neoadjuvant Therapy, Paclitaxel, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Receptors, Steroid, Trastuzumab, I-SPY 2 Consortium, Receptor, erbB-2, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.Patients and methodsI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.ResultsMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).ConclusionThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Published
2020

36. The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial

Author

McCreary, Erin K., Bariola, J. Ryan, Minnier, Tami E., Wadas, Richard J., Shovel, Judith A., Albin, Debbie, Marroquin, Oscar C., Kip, Kevin E., Collins, Kevin, Schmidhofer, Mark, Wisniewski, Mary Kay, Nace, David A., Sullivan, Colleen, Axe, Meredith, Meyers, Russell, Weissman, Alexandra, Garrard, William, Peck-Palmer, Octavia M., Wells, Alan, Bart, Robert D., Yang, Anne, Berry, Lindsay R., Berry, Scott, Crawford, Amy M., McGlothlin, Anna, Khadem, Tina, Linstrum, Kelsey, Montgomery, Stephanie K., Ricketts, Daniel, Kennedy, Jason N., Pidro, Caroline J., Haidar, Ghady, Snyder, Graham M., McVerry, Bryan J., Yealy, Donald M., Angus, Derek C., Nakayama, Anna, Zapf, Rachel L., Kip, Paula L., Seymour, Christopher W., and Huang, David T.

Published
2022
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37. Analytical validation and initial clinical testing of quantitative microscopic evaluation for PD-L1 and HLA I expression on circulating tumor cells from patients with non-small cell lung cancer

Author

Schehr, Jennifer L., Sethakorn, Nan, Schultz, Zachery D., Hernandez, Camila I., Bade, Rory M., Eyzaguirre, Diego, Singh, Anupama, Niles, David J., Henderson, Leslie, Warrick, Jay W., Berry, Scott M., Sundling, Kaitlin E., Beebe, David J., Leal, Ticiana A., and Lang, Joshua M.

Published
2022
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42. Development of the BOLT-2 Roughness Experiment for Flight.

Author

Berry, Scott A., Semper, Michael T., Riha, Andrew K., Mullen, C. Daniel, Reed, Helen L., Dufrene, Aaron T., and Fasel, Hermann F.

Abstract

A sounding rocket research flight called BOLT-2, which stands for Boundary Layer Turbulence 2, was initiated with the goal of studying hypersonic boundary-layer transition and turbulence. The BOLT-2 research vehicle is based on a three-dimensional geometry with concave surfaces and swept leading edges that provides two separate and distinct, also redundant, flowpaths for conducting measurements. One side of BOLT-2 is dedicated to smooth surface transition and turbulence, to better study the natural instability processes, whereas the other has been assigned to study forced transition and turbulence using discrete roughness trips. The present paper is intended to document the primary drivers and decisions made that lead up to finalizing the roughness-side experiment for the BOLT-2 flight. [ABSTRACT FROM AUTHOR]

Published
2024
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43. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients

Author

Adamson, Kathi, Albain, Kathy S., Asare, Adam L., Asare, Smita M., Balassanian, Ron, Beckwith, Heather, Berry, Scott M., Berry, Donald A., Boughey, Judy C., Buxton, Meredith B., Chen, Yunn-Yi, Chen, Beiyun, Chien, A. Jo, Chui, Stephen Y., Clark, Amy S., Clennell, Julia L., Datnow, Brian, DeMichele, Angela M., Duan, Xiuzhen, Edmiston, Kirsten K., Elias, Anthony D., Ellis, Erin D., Esserman, Laura L., Euhus, David M., Fadare, Oluwole, Fan, Fang, Feldman, Michael D, Forero-Torres, Andres, Haley, Barbara B., Han, Hyo S., Harada, Shuko, Haugen, Patricia, Helsten, Teresa, Hirst, Gillian L., Hylton, Nola M., Isaacs, Claudine, Kemmer, Kathleen, Khan, Qamar J., Khazai, Laila, Klein, Molly E., Krings, Gregor, Lang, Julie E., LeBeau, Lauren G., Leyland-Jones, Brian, Liu, Minetta C., Lo, Shelly, Lu, Janice, Magliocco, Anthony, Matthews, Jeffrey B., Melisko, Michelle E., Mhawech-Fauceglia, Paulette, Moulder, Stacy L., Murthy, Rashmi K., Nanda, Rita, Northfelt, Donald W., Ocal, Idris T., Olopade, Olufunmilayo, Pambuccian, Stefan, Paoloni, Melissa, Park, John W., Parker, Barbara A., Perlmutter, Jane, Peterson, Garry, Pusztai, Lajos, Rendi, Mara, Rugo, Hope S., Sahoo, Sunati, Sams, Sharon, Sanil, Ashish, Sattar, Husain, Schwab, Richard B., Singhrao, Ruby, Steeg, Katherine, Stringer-Reasor, Erica, Symmans, W. Fraser, Tawfik, Ossama, Tripathy, Debasish, Troxell, Megan L., van't Veer, Laura J., Venters, Sara J., Vinh, Tuyethoa, Viscusi, Rebecca K., Wallace, Anne M., Wei, Shi, Wilson, Amy, Yau, Christina, Yee, Douglas, Zeck, Jay C., Osdoit, Marie, van der Noordaa, Marieke, Shad, Sonal, Wei, Jane, de Croze, Diane, Hamy, Anne-Sophie, Laé, Marick, Reyal, Fabien, Sonke, Gabe S, Steenbruggen, Tessa G, van Seijen, Maartje, Wesseling, Jelle, Martín, Miguel, del Monte-Millán, Maria, López-Tarruella, Sara, Boughey, Judy C, Goetz, Matthew P, Hoskin, Tanya, Gould, Rebekah, Valero, Vicente, Edge, Stephen B, Abraham, Jean E, Bartlett, John M S, Caldas, Carlos, Dunn, Janet, Earl, Helena, Hayward, Larry, Hiller, Louise, Provenzano, Elena, Sammut, Stephen-John, Thomas, Jeremy S, Cameron, David, Graham, Ashley, Hall, Peter, Mackintosh, Lorna, Godwin, Andrew K, Schwensen, Kelsey, Sharma, Priyanka, DeMichele, Angela M, Cole, Kimberly, Kim, Mi-Ok, van 't Veer, Laura J, Esserman, Laura J, and Symmans, W Fraser

Published
2022
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44. Adaptive crossover designs for assessment of symptomatic treatments targeting behaviour in neurodegenerative disease: a phase 2 clinical trial of intranasal oxytocin for frontotemporal dementia (FOXY).

Author

Finger, Elizabeth, Berry, Scott, Cummings, Jeffrey, Coleman, Kristy, Hsiung, Robin, Feldman, Howard H, and Boxer, Adam

Subjects
Humans, Neurodegenerative Diseases, Oxytocin, Treatment Outcome, Administration, Intranasal, Cross-Over Studies, Sample Size, Social Behavior, Empathy, Neuropsychological Tests, Research Design, Female, Male, Frontotemporal Dementia, Apathy, Adaptive design, Clinical trial, Crossover design, Frontotemporal dementia, Neurosciences, Neurodegenerative, Dementia, Clinical Trials and Supportive Activities, Acquired Cognitive Impairment, Clinical Research, Brain Disorders, Mental Health, Aging, 6.1 Pharmaceuticals, Neurological, Medical and Health Sciences
Abstract

BackgroundThere are currently no treatments for empathy deficits in neuropsychiatric disorders. Acute administration of the hormone oxytocin has been associated with symptomatic improvements across animal models and several neuropsychiatric disorders, but results of the majority of oxytocin randomised controlled trials (RCTs) of longer duration have been negative or inconclusive. This lack of efficacy of may be due to rapid habituation to oxytocin with chronic dosing. The objective of the present study is to describe the design of a phase 2 adaptive randomised controlled crossover trial of intranasal oxytocin in frontotemporal dementia (FOXY) as an efficient model for future investigations of symptomatic treatments in neuropsychiatric and neurodegenerative disorders.MethodsStage 1 will identify which of three dose schedules is most promising based on change in the primary outcome measure, the Neuropsychiatric Inventory apathy/indifference domain score, over 6 weeks of treatment. In stage 2, additional patients are enrolled at the most promising dose for preliminary efficacy analysis when combined with stage 1 to determine if a phase 3 trial is warranted. Objective measures include facial expression recognition, cerebrospinal fluid (CSF) oxytocin levels, and behavioural ratings of videotaped interactions.ResultsA total of 20 patients per arm will be entered into stage 1 for a total of 60 patients. In stage 2, an additional 40 patients will be enrolled in the most promising dose arm.ConclusionsThe use of adaptive, crossover designs and inclusion of objective measures of change in CSF oxytocin levels and social behaviour will improve the efficiency and conclusiveness of RCTs of oxytocin and other symptomatic treatments in neuropsychiatric disorders.Trial registrationClinicalTrials.gov, NCT03260920 . Registered on August 24, 2017.

Published
2018

45. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial

Author

Venook, Alan P, Niedzwiecki, Donna, Lenz, Heinz-Josef, Innocenti, Federico, Fruth, Briant, Meyerhardt, Jeffrey A, Schrag, Deborah, Greene, Claire, O'Neil, Bert H, Atkins, James Norman, Berry, Scott, Polite, Blase N, O'Reilly, Eileen M, Goldberg, Richard M, Hochster, Howard S, Schilsky, Richard L, Bertagnolli, Monica M, El-Khoueiry, Anthony B, Watson, Peter, Benson, Al B, Mulkerin, Daniel L, Mayer, Robert J, and Blanke, Charles

Subjects
Cancer, Clinical Trials and Supportive Activities, Clinical Research, Colo-Rectal Cancer, Digestive Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Camptothecin, Canada, Cetuximab, Colorectal Neoplasms, Disease-Free Survival, Female, Fluorouracil, Genes, ras, Humans, Kaplan-Meier Estimate, Leucovorin, Male, Middle Aged, Organoplatinum Compounds, Treatment Outcome, United States, Medical and Health Sciences, General & Internal Medicine
Abstract

ImportanceCombining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.ObjectiveTo determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.Design, setting, and participantsPatients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015.InterventionsCetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient.Main outcomes and measuresThe primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response.ResultsAmong 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13).Conclusions and relevanceAmong patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.Trial registrationclinicaltrials.gov identifier: NCT00265850.

Published
2017

46. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Author

Salloway, Stephen, Farlow, Martin, McDade, Eric, Clifford, David B., Wang, Guoqiao, Llibre-Guerra, Jorge J., Hitchcock, Janice M., Mills, Susan L., Santacruz, Anna M., Aschenbrenner, Andrew J., Hassenstab, Jason, Benzinger, Tammie L. S., Gordon, Brian A., Fagan, Anne M., Coalier, Kelley A., Cruchaga, Carlos, Goate, Alison A., Perrin, Richard J., Xiong, Chengjie, Li, Yan, Morris, John C., Snider, B. Joy, Mummery, Catherine, Surti, G. Mustafa, Hannequin, Didier, Wallon, David, Berman, Sarah B., Lah, James J., Jimenez-Velazquez, Ivonne Z., Roberson, Erik D., van Dyck, Christopher H., Honig, Lawrence S., Sánchez-Valle, Raquel, Brooks, William S., Gauthier, Serge, Galasko, Douglas R., Masters, Colin L., Brosch, Jared R., Hsiung, Ging-Yuek Robin, Jayadev, Suman, Formaglio, Maité, Masellis, Mario, Clarnette, Roger, Pariente, Jérémie, Dubois, Bruno, Pasquier, Florence, Jack, Jr, Clifford R., Koeppe, Robert, Snyder, Peter J., Aisen, Paul S., Thomas, Ronald G., Berry, Scott M., Wendelberger, Barbara A., Andersen, Scott W., Holdridge, Karen C., Mintun, Mark A., Yaari, Roy, Sims, John R., Baudler, Monika, Delmar, Paul, Doody, Rachelle S., Fontoura, Paulo, Giacobino, Caroline, Kerchner, Geoffrey A., and Bateman, Randall J.

Published
2021
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47. A minimal common outcome measure set for COVID-19 clinical research

Author

Marshall, John C, Murthy, Srinivas, Diaz, Janet, Adhikari, N K, Angus, Derek C, Arabi, Yaseen M, Baillie, Kenneth, Bauer, Michael, Berry, Scott, Blackwood, Bronagh, Bonten, Marc, Bozza, Fernando, Brunkhorst, Frank, Cheng, Allen, Clarke, Mike, Dat, Vu Quoc, de Jong, Menno, Denholm, Justin, Derde, Lennie, Dunning, Jake, Feng, Xiaobin, Fletcher, Tom, Foster, Nadine, Fowler, Rob, Gobat, Nina, Gomersall, Charles, Gordon, Anthony, Glueck, Thomas, Harhay, Michael, Hodgson, Carol, Horby, Peter, Kim, YaeJean, Kojan, Richard, Kumar, Bharath, Laffey, John, Malvey, Denis, Martin-Loeches, Ignacio, McArthur, Colin, McAuley, Danny, McBride, Stephen, McGuinness, Shay, Merson, Laura, Morpeth, Susan, Needham, Dale, Netea, Mihai, Oh, Myoung-Don, Phyu, Sabai, Piva, Simone, Qiu, Ruijin, Salisu-Kabara, Halima, Shi, Lei, Shimizu, Naoki, Sinclair, Jorge, Tong, Steven, Turgeon, Alexis, Uyeki, Tim, van de Veerdonk, Frank, Webb, Steve, Williamson, Paula, Wolf, Timo, and Zhang, Junhua

Published
2020
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50. Supplementary Table S3 from Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial—Efficacy and Biomarker Discovery

Author

Albain, Kathy S., primary, Yau, Christina, primary, Petricoin, Emanuel F., primary, Wolf, Denise M., primary, Lang, Julie E., primary, Chien, A. Jo, primary, Haddad, Tufia, primary, Forero-Torres, Andres, primary, Wallace, Anne M., primary, Kaplan, Henry, primary, Pusztai, Lajos, primary, Euhus, David, primary, Nanda, Rita, primary, Elias, Anthony D., primary, Clark, Amy S., primary, Godellas, Constantine, primary, Boughey, Judy C., primary, Isaacs, Claudine, primary, Tripathy, Debu, primary, Lu, Janice, primary, Yung, Rachel L., primary, Gallagher, Rosa I., primary, Wulfkuhle, Julia D., primary, Brown-Swigart, Lamorna, primary, Krings, Gregor, primary, Chen, Yunn Yi, primary, Potter, David A., primary, Stringer-Reasor, Erica, primary, Blair, Sarah, primary, Asare, Smita M., primary, Wilson, Amy, primary, Hirst, Gillian L., primary, Singhrao, Ruby, primary, Buxton, Meredith, primary, Clennell, Julia L., primary, Sanil, Ashish, primary, Berry, Scott, primary, Asare, Adam L., primary, Matthews, Jeffrey B., primary, DeMichele, Angela M., primary, Hylton, Nola M., primary, Melisko, Michelle, primary, Perlmutter, Jane, primary, Rugo, Hope S., primary, Symmans, W. Fraser, primary, van't Veer, Laura J., primary, Yee, Douglas, primary, Berry, Donald A., primary, and Esserman, Laura J., primary

Published
2024
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