Journal article
Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.
- Lewin J Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Soria JC Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Stathis A Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Delord JP Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Peters S Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Awada A Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Aftimos PG Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Bekradda M Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Rezai K Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Zeng Z Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Hussain A Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Perez S Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Siu LL Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- Massard C Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.
- 2018-05-08
Published in:
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 2018
Acetanilides
Adult
Aged
Antineoplastic Agents
Dose-Response Relationship, Drug
Female
Heterocyclic Compounds, 3-Ring
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Young Adult
English
PURPOSE
Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study.
PATIENTS AND METHODS
Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose.
RESULTS
Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption.
CONCLUSION
The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.
Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study.
PATIENTS AND METHODS
Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose.
RESULTS
Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption.
CONCLUSION
The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1200/JCO.2018.78.2292
- PMID 29733771
- Persistent URL
- https://sonar.ch/global/documents/20457
Statistics
Document views: 125
File downloads: