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1. Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson’s Disease Motor Progression

Author

Holly Jackson, Judith Anzures-Cabrera, Kirsten I. Taylor, Gennaro Pagano, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Guenter Hoeglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Brit Mollenhauer, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Werner Poewe, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Tanya Simuni, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Azad Bonni, Edilio Borroni, Anne Boulay, Markus Britschgi, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Rachelle Doody, Juergen Dukart, Giulia D’Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Paulo Fontoura, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Martin Koller, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Maddalena Marchesi, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Tania Nikolcheva, Susanne Ostrowitzki GP, Benedicte Passmard, Agnes Poirier, Anke Post, Megana Prasad, Nathalie Pross, Tiffany Quock, Benedicte Ricci, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Jeff Sevigny, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Hanno Svoboda KT, Radhika Tripuraneni, Dylan Trundell, Daniel Umbricht, Lynne Verselis, Annamarie Vogt, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
PASADENA, PPMI (Parkinson’s Progression Markers Initiative), Parkinson’s disease, progression predictors, ridge regression, disease stage, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Currently, no treatments available for Parkinson’s disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson’s Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.

Published
2021
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2. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data

Author

Gennaro Pagano, Frank G. Boess, Kirsten I. Taylor, Benedicte Ricci, Brit Mollenhauer, Werner Poewe, Anne Boulay, Judith Anzures-Cabrera, Annamarie Vogt, Maddalena Marchesi, Anke Post, Tania Nikolcheva, Gene G. Kinney, Wagner M. Zago, Daniel K. Ness, Hanno Svoboda, Markus Britschgi, Susanne Ostrowitzki, Tanya Simuni, Kenneth Marek, Martin Koller, Jeff Sevigny, Rachelle Doody, Paulo Fontoura, Daniel Umbricht, Azad Bonni, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Günter Höglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Edilio Borroni, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Juergen Dukart, Giulia D'Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Benedicte Passmard, Agnes Poirier, Megana Prasad, Nathalie Pross, Tiffany Quock, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Kirsten Taylor, Radhika Tripuraneni, Dylan Trundell, Lynne Verselis, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
Parkinson's disease, alpha-synuclein (α-syn), prasinezumab, monoclonal antibodies, disease progression, MDS-UPDRS = Movement Disorder Society—Unified Parkinson's Disease Rating Scale, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial Registration: NCT03100149.

Published
2021
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3. MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia

Author

Rebeca Rodríguez-Veiga, Benjamin M. Beckermann, Annabelle Monnet, Olivier Catalani, Pau Montesinos, Norbert Vey, Andrew H. Wei, Sung-Soo Yoon, Cristina Papayannidis, Christoph Röllig, Katia Gamel, Giovanni Martinelli, Aaron Park, Marina Konopleva, Jordi Esteve, Pierre Fenaux, and Christian Recher

Subjects
p53, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Pyrrolidines, Adolescent, Population, acute myeloid leukemia, trial in progress, Placebo, idasanutlin, 03 medical and health sciences, 0302 clinical medicine, AML, MDM2, Refractory, cytarabine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, para-Aminobenzoates, medicine, Clinical endpoint, Humans, IDASANUTLIN, education, neoplasms, education.field_of_study, business.industry, Remission Induction, Cytarabine, Myeloid leukemia, Proto-Oncogene Proteins c-mdm2, General Medicine, Interim analysis, MIRROS, relapsed, refractory, Leukemia, Myeloid, Acute, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Tumor Suppressor Protein p53, business, medicine.drug
Abstract

Patients with refractory or relapsed acute myeloid leukemia (R/R AML) have a poor prognosis, with a high unmet medical need. Idasanutlin is a small-molecule inhibitor of MDM2, a negative regulator of tumor suppressor p53. By preventing the p53–MDM2 interaction, idasanutlin allows for p53 activation, particularly in patients with TP53 wild-type (WT) status. MIRROS (NCT02545283) is a randomized Phase III trial evaluating idasanutlin + cytarabine versus placebo + cytarabine in R/R AML. The primary end point is overall survival in the TP53-WT population. Secondary end points include complete remission rate (cycle 1), overall remission rate (cycle 1) and event-free survival in the TP53-WT population. MIRROS has an innovative design that integrates a stringent interim analysis for futility; continuation criteria were met in mid-2017 and accrual is ongoing. Trial registration number: NCT02545283

Published
2020

4. Combination of Idasanutlin, Venetoclax and Obinutuzumab in Patients with Relapsed or Refractory (R/R) Non-Hodgkin Lymphoma (NHL): Results from a Phase I/II Study

Author

Don A. Stevens, Yann Nouet, Ye Zhao, Sonali M. Smith, Young Rok Do, Amanda Johnston, Manali Kamdar, Mark P. Hertzberg, Annabelle Monnet, Jin Seok Kim, Frank Kroschinsky, Bradley Augustson, James Edwards, and Viktoriya Marinova

Subjects
Oncology, medicine.medical_specialty, Venetoclax, business.industry, Immunology, Cell Biology, Hematology, Biochemistry, chemistry.chemical_compound, Phase i ii, Refractory, chemistry, Obinutuzumab, Internal medicine, medicine, Hodgkin lymphoma, In patient, IDASANUTLIN, business
Abstract

Background Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common indolent and aggressive B-cell lymphomas, respectively. Although the combination of anti-CD20 therapies rituximab (R) or obinutuzumab (G) with chemotherapy has led to improved patient (pt) outcomes, R/R disease remains a challenge, with a high unmet need. The potent and selective MDM2 antagonist idasanutlin (idasa) activates the p53 pathway, leading to anti-tumor activity. The BCL-2 inhibitor venetoclax (ven) has shown clinical activity in hematologic diseases including R/R NHL. In a Phase Ib/II study (NCT02624986), idasa could be safely combined in a doublet treatment (tx) regimen with R or G in R/R FL or DLBCL pts. Here we report the tolerability, safety and preliminary efficacy of the triplet tx regimen of idasa plus ven and G in R/R NHL pts. Methods BH39147 (NCT03135262) was an open-label, multicenter, non-randomized, Phase Ib/II study with a dose-escalation phase followed by an expansion phase. The dose-escalation phase evaluated idasa and ven combined with G in all pts (FL and DLBCL) until the maximum tolerated dose (MTD) was reached. Idasa and ven dose escalations started at 100 and 200 mg PO QD, respectively, on days 1-5 of each 28-day cycle (safety cohort); in subsequent cohorts, ven was given on days 1-10 of each cycle. G was given at a fixed dose of 1000 mg IV on days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles. Pts received 6 cycles of induction tx. The primary objective of the dose-escalation phase was to determine recommended Phase II doses for idasa and ven in combination with G. Efficacy objectives included evaluating the complete response (CR) rate at the end of induction (EOI) per investigator based on PET-CT. The trial was stopped prior to initiation of the expansion phase; results are presented for the dose-escalation cohorts evaluating idasa plus ven and G. Results Of the 29 pts enrolled, 14 each had a diagnosis of FL or DLBCL at study entry, and 1 had an unknown diagnosis at study entry that was later confirmed as FL. The median age was 70 y (range, 25-82), 58.6% of pts were male, and 67.9% had an ECOG PS of 1 or 2. The majority of pts had advanced-stage disease at enrollment, with 58.6% having received ≥ 3 lines of prior anti-lymphoma therapy; 17.2% and 24.1% of pts had received 1 and 2 prior lines of tx, respectively. Median (range) tx durations during induction were 1.3 mo (0-6) for idasa, 1.5 mo (0-7) for ven and 1.5 mo (0-6) for G; post-induction median (range) tx durations (n = 4) were 3.8 mo (0-4), 3.8 mo (0-4) and 8.4 mo (0-11), respectively. The safety-evaluable population was composed of 29 pts. Grade 3/4 adverse events (AEs) occurred in 86.2% of pts, with neutropenia (79.3%), thrombocytopenia (62.1%), leukopenia (27.6%) and anemia (20.7%) as the most common. No Grade 5 AEs were reported. Serious AEs occurred in 48.3% of pts and were most commonly neutropenia (10.3%). AEs led to treatment discontinuation in 41.4% of pts, with thrombocytopenia (17.2%) and neutropenia (13.8%) being the most common. AEs related to idasa, ven and G were reported in 86.2%, 89.7% and 79.3% of pts, respectively. Dose-limiting toxicities were reported in 4 pts (13.8%): neutropenia (n = 3; 10.3%), hyperbilirubinemia (n = 1; 3.4%) and transaminitis (n = 1; 3.4%). The MTD for idasa was determined to be 150 mg in combination with 200-mg ven and G and 100 mg in combination with 400-mg ven and G. Preliminary efficacy data are shown in the table. Among all pts, 20.7% (FL, n = 5; DLBCL, n = 1) had a CR at EOI per investigator (PET-CT) based on modified Lugano 2014 criteria. Per investigator based on Lugano 2014 criteria, the CR rate at EOI (CT) was 13.8% (FL, n = 3; DLBCL, n = 1), and the complete metabolic response rate at EOI (PET-CT) was 24.1% (FL, n = 6; DLBCL, n = 1). Conclusions This study successfully showed the combinability of idasa and ven with an anti-CD20 agent. MTDs were determined for idasa and ven in combination with G in FL and DLBCL pts. No new safety signals related to any of the study drugs were identified, and the observed safety profiles were consistent with those of each individual study drug. While the combination is feasible and promising, other agents and approaches in the field make this combination less likely to proceed further. As a consequence, this trial has been discontinued following the dose-escalation/proof-of-concept phase to focus on new tx combinations. Figure Disclosures Kamdar: Roche:Research Funding.Augustson:Roche:Other: Support of parent study and funding of editorial support.Edwards:Roche:Other: Support of parent study and funding of editorial support.Hertzberg:Roche:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support;Gilead:Membership on an entity's Board of Directors or advisory committees;MSD:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria;BMS:Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees.Johnston:Roche:Other: Support of parent study and funding of editorial support.Kim:Alexion Pharmaceuticals Inc.:Honoraria, Research Funding.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding;Gilead:Consultancy.Smith:TG Therapeutics:Consultancy, Research Funding;Genentech/Roche:Consultancy, Other: Support of parent study and funding of editorial support, Research Funding;BMS:Consultancy;Karyopharm:Consultancy, Research Funding;FortySeven:Research Funding;Pharmacyclics:Research Funding;Acerta:Research Funding;Janssen:Consultancy;Celgene:Consultancy, Research Funding.Stevens:Amgen, MorphoSys:Consultancy.Monnet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Zhao:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Nouet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Marinova:Roche:Current Employment, Other: Support of parent study and funding of editorial support.

Published
2020

5. Integrating Phase 2 into Phase 3 based on an Intermediate Endpoint While Accounting for a Cure Proportion -- with an Application to the Design of a Clinical Trial in Acute Myeloid Leukemia

Author

Kaspar Rufibach, Dominik Heinzmann, and Annabelle Monnet

Subjects
Statistics and Probability, FOS: Computer and information sciences, medicine.medical_specialty, Endpoint Determination, 01 natural sciences, Phase (combat), Statistics - Applications, law.invention, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Clinical Trials, Phase II as Topic, Randomized controlled trial, Drug Development, law, Interim, medicine, Clinical endpoint, Humans, Pharmacology (medical), Computer Simulation, Applications (stat.AP), 030212 general & internal medicine, 0101 mathematics, Intensive care medicine, Randomized Controlled Trials as Topic, Pharmacology, Models, Statistical, business.industry, Uncertainty, Myeloid leukemia, Intermediate endpoint, Interim analysis, Clinical trial, Survival Rate, Leukemia, Myeloid, Acute, Clinical Trials, Phase III as Topic, Research Design, Data Interpretation, Statistical, 62P10, business
Abstract

For a trial with primary endpoint overall survival for a molecule with curative potential, statistical methods that rely on the proportional hazards assumption may underestimate the power and the time to final analysis. We show how a cure proportion model can be used to get the necessary number of events and appropriate timing via simulation. If Phase 1 results for the new drug are exceptional and/or the medical need in the target population is high, a Phase 3 trial might be initiated after Phase 1. Building in a futility interim analysis into such a pivotal trial may mitigate the uncertainty of moving directly to Phase 3. However, if cure is possible, overall survival might not be mature enough at the interim to support a futility decision. We propose to base this decision on an intermediate endpoint that is sufficiently associated with survival. Planning for such an interim can be interpreted as making a randomized Phase 2 trial a part of the pivotal trial: if stopped at the interim, the trial data would be analyzed and a decision on a subsequent Phase 3 trial would be made. If the trial continues at the interim then the Phase 3 trial is already underway. To select a futility boundary, a mechanistic simulation model that connects the intermediate endpoint and survival is proposed. We illustrate how this approach was used to design a pivotal randomized trial in acute myeloid leukemia, discuss historical data that informed the simulation model, and operational challenges when implementing it., Comment: 23 pages, 3 figures, 3 tables. All code is available on github: https://github.com/numbersman77/integratePhase2.git

Published
2019
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6. Alectinib in Crizotinib-Refractory ALK-Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study

Author

Bogdana Balas, Alessandra Bearz, Ramaswamy Govindan, Peter N. Morcos, James Chih-Hsin Yang, Luigi De Petris, Annabelle Monnet, Brett G.M. Hughes, Jin Seok Ahn, Tarek Mekhail, Denis Moro-Sibilot, Ali Zeaiter, Alexander I. Spira, Hervé Lena, Santiago Viteri Ramirez, Sai-Hong Ignatius Ou, Dong Wan Kim, and Walter Bordogna

Subjects
Adult, Male, 0301 basic medicine, Alectinib, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Brigatinib, Pyridines, medicine.drug_class, Carbazoles, Administration, Oral, Gastroenterology, Disease-Free Survival, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Crizotinib, Piperidines, Carcinoma, Non-Small-Cell Lung, Internal medicine, medicine, Humans, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, Lung cancer, Protein Kinase Inhibitors, Aged, Ceritinib, business.industry, Receptor Protein-Tyrosine Kinases, Middle Aged, medicine.disease, Lorlatinib, Surgery, ALK inhibitor, Treatment Outcome, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Disease Progression, Pyrazoles, Female, business, medicine.drug
Abstract

Purpose Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Patients and Methods Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Results Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Published
2016

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