PHARMACOKINETIC EXPOSURE EQUIVALENCE AND PRELIMINARY EFFICACY AND SAFETY FROM A RANDOMIZED CROSS OVER PHASE 3 STUDY OF AN ORAL HYPOMETHYLATING AGENT DEC-C COMPARED TO IV DECITABINE IN AML PATIENTS
Author(s): ,
Klaus Geissler
Affiliations:
Clinic Hietzing,Vienna,Autriche;Clinic Hietzing,Vienna,Österreich;Clinic Hietzing,Vienna,Austria;Clinic Hietzing,Vienna,Austria;Clinic Hietzing,Vienna,Austria;Clinic Hietzing,Vienna,Oostenrijk;Clinic Hietzing,Vienna,Áustria;Clinic Hietzing,Vienna,Австрия;Clinic Hietzing,Vienna,Österrike
,
Zdenek Koristek
Affiliations:
University Hospital Ostrava,Ostrava,Tchèque, République;University Hospital Ostrava,Ostrava,Tschechische Republik;University Hospital Ostrava,Ostrava,Rep. Ceca;University Hospital Ostrava,Ostrava,Czech;University Hospital Ostrava,Ostrava,República Checa;University Hospital Ostrava,Ostrava,Tsjechische Republiek;University Hospital Ostrava,Ostrava,República Tcheca;University Hospital Ostrava,Ostrava
,
Teresa Bernal del Castillo
Affiliations:
Hospital Universitario Central de Asturias,Oviedo,Espagne;Hospital Universitario Central de Asturias,Oviedo,Spanien;Hospital Universitario Central de Asturias,Oviedo,Spagna;Hospital Universitario Central de Asturias,Oviedo,Spain;Hospital Universitario Central de Asturias,Oviedo,España;Hospital Universitario Central de Asturias,Oviedo,Spanje;Hospital Universitario Central de Asturias,Oviedo,Espanha
,
Jan Novák
Affiliations:
Department of Haematology, 3rd Faculty of Medicine,Charles University and Faculty Hospital Kralovske Vinohrady,Prague,Tchèque, République;Department of Haematology, 3rd Faculty of Medicine,Charles University and Faculty Hospital Kralovske Vinohrady,Prague,Tschechische Republik;Department of Haematology, 3rd Faculty of Medicine,Charles University and Faculty Hospital Kralovske Vinohrady,Prague,Rep.
,
Gabriela Rodriguez Macias
Affiliations:
Hospital General Universitario Gregorio Marañón,Madrid,Espagne;Hospital General Universitario Gregorio Marañón,Madrid,Spanien;Hospital General Universitario Gregorio Marañón,Madrid,Spagna;Hospital General Universitario Gregorio Marañón,Madrid,Spain;Hospital General Universitario Gregorio Marañón,Madrid,España;Hospital General Universitario Gregorio Marañón,Madrid,Spanje;Hospital General Universita
,
Stephan K Metzelder
Affiliations:
Philipps-Universität Marburg,Marburg,Allemagne;Philipps-Universität Marburg,Marburg,Deutschland;Philipps-Universität Marburg,Marburg,Germania;Philipps-Universität Marburg,Marburg,Germany;Philipps-Universität Marburg,Marburg,Alemania;Philipps-Universität Marburg,Marburg,Duitsland;Philipps-Universität Marburg,Marburg,Alemanha;Philipps-Universität Marburg,Marburg,Германия;Philipps-Universität Marburg
,
Arpad Illes
Affiliations:
Division of Haematologoy, Department of Internal Medicine, Faculty of Medicine,University of Debrecen,Debreccen,Hongrie;Division of Haematologoy, Department of Internal Medicine, Faculty of Medicine,University of Debrecen,Debreccen,Ungarn;Division of Haematologoy, Department of Internal Medicine, Faculty of Medicine,University of Debrecen,Debreccen,Ungheria;Division of Haematologoy, Department of
,
Agnes Nagy
Affiliations:
1st Department of Internal Medicine,University of Pécs,Pécs,Hongrie;1st Department of Internal Medicine,University of Pécs,Pécs,Ungarn;1st Department of Internal Medicine,University of Pécs,Pécs,Ungheria;1st Department of Internal Medicine,University of Pécs,Pécs,Hungary;1st Department of Internal Medicine,University of Pécs,Pécs,Hungría;1st Department of Internal Medicine,University of Pécs,Pécs,
,
Jiri Mayer
Affiliations:
Fakultní Nemocnice,Brno,Tchèque, République;Fakultní Nemocnice,Brno,Tschechische Republik;Fakultní Nemocnice,Brno,Rep. Ceca;Fakultní Nemocnice,Brno,Czech;Fakultní Nemocnice,Brno,República Checa;Fakultní Nemocnice,Brno,Tsjechische Republiek;Fakultní Nemocnice,Brno,República Tcheca;Fakultní Nemocnice,Brno,Чехия;Fakultní Nemocnice,Brno,Tjeckien
,
Montserrat Arnan
Affiliations:
Hematology Department,Servei d'Hematologia, Institut Català d'Oncologia, Hospital Duran i Reynals, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat,Barcelona,Espagne;Hematology Department,Servei d'Hematologia, Institut Català d'Oncologia, Hospital Duran i Reynals, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de B
,
Mary-Margaret Keating
Affiliations:
Queen Elizabeth II (QEII) Health Sciences Centre,Halifax, Nova Scotia,Canada;Queen Elizabeth II (QEII) Health Sciences Centre,Halifax, Nova Scotia,Kanada;Queen Elizabeth II (QEII) Health Sciences Centre,Halifax, Nova Scotia,Canada;Queen Elizabeth II (QEII) Health Sciences Centre,Halifax, Nova Scotia,Canada;Queen Elizabeth II (QEII) Health Sciences Centre,Halifax, Nova Scotia,Canadá;Queen Elizabeth
,
Jürgen Krauter
Affiliations:
Städtisches Klinikum Braunschweig,Braunschweig,Allemagne;Städtisches Klinikum Braunschweig,Braunschweig,Deutschland;Städtisches Klinikum Braunschweig,Braunschweig,Germania;Städtisches Klinikum Braunschweig,Braunschweig,Germany;Städtisches Klinikum Braunschweig,Braunschweig,Alemania;Städtisches Klinikum Braunschweig,Braunschweig,Duitsland;Städtisches Klinikum Braunschweig,Braunschweig,Alemanha;Städ
,
Monia Lunghi
Affiliations:
Azienda Ospedaliero-Universitaria Maggiore della Carità Novara,Novara,Italie;Azienda Ospedaliero-Universitaria Maggiore della Carità Novara,Novara,Italien;Azienda Ospedaliero-Universitaria Maggiore della Carità Novara,Novara,Italia;Azienda Ospedaliero-Universitaria Maggiore della Carità Novara,Novara,Italy;Azienda Ospedaliero-Universitaria Maggiore della Carità Novara,Novara,Italia;Azienda Ospedal
,
Nicola Stefano Fracchiolla
Affiliations:
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano,Milano,Italie;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano,Milano,Italien;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano,Milano,Italia;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano,Milano,Italy;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano,Mila
,
Uwe Platzbecker
Affiliations:
University Hospital Leipzig,Leipzig,Allemagne;University Hospital Leipzig,Leipzig,Deutschland;University Hospital Leipzig,Leipzig,Germania;University Hospital Leipzig,Leipzig,Germany;University Hospital Leipzig,Leipzig,Alemania;University Hospital Leipzig,Leipzig,Duitsland;University Hospital Leipzig,Leipzig,Alemanha;University Hospital Leipzig,Leipzig,Германия;University Hospital Leipzig,Leipzig,
,
Valeria Santini
Affiliations:
MDS Unit,AOU Careggi, DMSC, University of Florence ,Firenze,Italie;MDS Unit,AOU Careggi, DMSC, University of Florence ,Firenze,Italien;MDS Unit,AOU Careggi, DMSC, University of Florence ,Firenze,Italia;MDS Unit,AOU Careggi, DMSC, University of Florence ,Firenze,Italy;MDS Unit,AOU Careggi, DMSC, University of Florence ,Firenze,Italia;MDS Unit,AOU Careggi, DMSC, University of Florence ,Firenze,Itali
,
Yuri Sano
Affiliations:
Astex Pharmaceuticals, Inc.,Pleasanton,États-unis;Astex Pharmaceuticals, Inc.,Pleasanton,Vereinigte Staaten;Astex Pharmaceuticals, Inc.,Pleasanton,Stati Uniti;Astex Pharmaceuticals, Inc.,Pleasanton,United States;Astex Pharmaceuticals, Inc.,Pleasanton,Estados Unidos;Astex Pharmaceuticals, Inc.,Pleasanton,Verenigde Staten;Astex Pharmaceuticals, Inc.,Pleasanton,Estados Unidos;Astex Pharmaceuticals, I
,
Aram Oganesian
Affiliations:
Astex Pharmaceuticals, Inc.,Pleasanton,États-unis;Astex Pharmaceuticals, Inc.,Pleasanton,Vereinigte Staaten;Astex Pharmaceuticals, Inc.,Pleasanton,Stati Uniti;Astex Pharmaceuticals, Inc.,Pleasanton,United States;Astex Pharmaceuticals, Inc.,Pleasanton,Estados Unidos;Astex Pharmaceuticals, Inc.,Pleasanton,Verenigde Staten;Astex Pharmaceuticals, Inc.,Pleasanton,Estados Unidos;Astex Pharmaceuticals, I
,
Harold Keer
Affiliations:
Astex Pharmaceuticals, Inc.,Pleasanton,États-unis;Astex Pharmaceuticals, Inc.,Pleasanton,Vereinigte Staaten;Astex Pharmaceuticals, Inc.,Pleasanton,Stati Uniti;Astex Pharmaceuticals, Inc.,Pleasanton,United States;Astex Pharmaceuticals, Inc.,Pleasanton,Estados Unidos;Astex Pharmaceuticals, Inc.,Pleasanton,Verenigde Staten;Astex Pharmaceuticals, Inc.,Pleasanton,Estados Unidos;Astex Pharmaceuticals, I
Michael Lübbert
Affiliations:
Universitaetsklinikum Freiburg,Freiburg,Allemagne;Universitaetsklinikum Freiburg,Freiburg,Deutschland;Universitaetsklinikum Freiburg,Freiburg,Germania;Universitaetsklinikum Freiburg,Freiburg,Germany;Universitaetsklinikum Freiburg,Freiburg,Alemania;Universitaetsklinikum Freiburg,Freiburg,Duitsland;Universitaetsklinikum Freiburg,Freiburg,Alemanha;Universitaetsklinikum Freiburg,Freiburg,Германия;Univ
(Abstract release date: 05/12/22) EHA Library. Sano Y. 06/10/22; 357436; P573
Yuri Sano
Yuri Sano
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P573

Type: Poster presentation

Session title: Acute myeloid leukemia - Clinical

Background
Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. ASTX727 (DEC-C) is a fixed dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, a novel cytidine deaminase inhibitor (CDAi). In clinical trials with myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) patients, DEC-C provides DEC exposures that are equivalent to IV DEC at the approved dose of 20 mg/m2 daily×5 and is approved as INQOVI® in the US, Canada, and Australia. 

Aims

To demonstrate DEC exposure bioequivalence of oral DEC-C and IV-DEC and generate clinical data using DEC-C in AML patients.

Methods

The ASCERTAIN study was a randomized cross over design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare PK [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 onwards until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria.

Results

89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%) and intermediate-risk in 45 (51.7%) patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV DEC and DEC-C cycles, and the DEC AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, anemia, febrile neutropenia, neutropenia, and pneumonia). As of the data cutoff date (10 SEP 2021), median follow up was 7.95 months (IQR 6.11-11.86). Of the 77 patients who had ≥6 months of follow up or discontinued treatment, the best response was complete response (CR) in 17 (22.1%, 95% CI: 13.4, 33.0%). In addition, 4 patients (5.2%) had CR with incomplete blood cell count recovery (CRi), with 1 patient (1.3%) who had CR with incomplete platelet recovery (CRp), resulting in composite response rate [CR + CRp] of 23.4% [18/77 patients, 95% CI: 14.5, 34.4%]. These results obtained with DEC-C are consistent with those observed for IV DEC. Based on preliminary and limited study follow-up with ~46% censored observations, the median survival was approximately 7.9 months (95% CI: 5.9, 13.0).

Conclusion

This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that the oral FDC of DEC-C (35mg/100 mg) resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m2 over 5 days. In addition, safety findings and preliminary clinical activity is also consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV decitabine Daily×5 regimen.

Keyword(s): AML, Decitabine, Hypomethylating agents, Oral

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P573

Type: Poster presentation

Session title: Acute myeloid leukemia - Clinical

Background
Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. ASTX727 (DEC-C) is a fixed dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, a novel cytidine deaminase inhibitor (CDAi). In clinical trials with myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) patients, DEC-C provides DEC exposures that are equivalent to IV DEC at the approved dose of 20 mg/m2 daily×5 and is approved as INQOVI® in the US, Canada, and Australia. 

Aims

To demonstrate DEC exposure bioequivalence of oral DEC-C and IV-DEC and generate clinical data using DEC-C in AML patients.

Methods

The ASCERTAIN study was a randomized cross over design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare PK [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 onwards until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria.

Results

89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%) and intermediate-risk in 45 (51.7%) patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV DEC and DEC-C cycles, and the DEC AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, anemia, febrile neutropenia, neutropenia, and pneumonia). As of the data cutoff date (10 SEP 2021), median follow up was 7.95 months (IQR 6.11-11.86). Of the 77 patients who had ≥6 months of follow up or discontinued treatment, the best response was complete response (CR) in 17 (22.1%, 95% CI: 13.4, 33.0%). In addition, 4 patients (5.2%) had CR with incomplete blood cell count recovery (CRi), with 1 patient (1.3%) who had CR with incomplete platelet recovery (CRp), resulting in composite response rate [CR + CRp] of 23.4% [18/77 patients, 95% CI: 14.5, 34.4%]. These results obtained with DEC-C are consistent with those observed for IV DEC. Based on preliminary and limited study follow-up with ~46% censored observations, the median survival was approximately 7.9 months (95% CI: 5.9, 13.0).

Conclusion

This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that the oral FDC of DEC-C (35mg/100 mg) resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m2 over 5 days. In addition, safety findings and preliminary clinical activity is also consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV decitabine Daily×5 regimen.

Keyword(s): AML, Decitabine, Hypomethylating agents, Oral

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies