A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

© The Author 2015. Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Patients and methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P <0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P <0.001) and activated CD86+CD27+ memory B cells (P
Original languageEnglish
Pages (from-to)2483-2490
JournalAnnals of Oncology
Volume26
Issue number12
DOIs
Publication statusPublished - 2015

Fingerprint

Pemetrexed
Cisplatin
Clinical Trials
Antibodies
B-Lymphocytes
Maximum Tolerated Dose
Splenic Infarction
Drug Therapy
Hyponatremia
CP-870,893
Malignant Mesothelioma
Disease-Free Survival
Flow Cytometry
Biomarkers
Cytokines

Cite this

@article{4bf25a6024ea467992758c9845da3704,
title = "A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma",
abstract = "{\circledC} The Author 2015. Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Patients and methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80{\%}) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40{\%}) and 9 stable disease (53{\%}) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P <0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P <0.001) and activated CD86+CD27+ memory B cells (P",
author = "Anna Nowak and Alistair Cook and Alison Mcdonnell and Michael Millward and Jenette Creaney and Roslyn Francis and A. Hasani and A. Segal and Arthur Musk and Berwin Turlach and Melanie Mccoy and Bruce Robinson and Richard Lake",
year = "2015",
doi = "10.1093/annonc/mdv387",
language = "English",
volume = "26",
pages = "2483--2490",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "OXFORD UNIV PRESS UNITED KINGDOM",
number = "12",

}

TY - JOUR

T1 - A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma

AU - Nowak, Anna

AU - Cook, Alistair

AU - Mcdonnell, Alison

AU - Millward, Michael

AU - Creaney, Jenette

AU - Francis, Roslyn

AU - Hasani, A.

AU - Segal, A.

AU - Musk, Arthur

AU - Turlach, Berwin

AU - Mccoy, Melanie

AU - Robinson, Bruce

AU - Lake, Richard

PY - 2015

Y1 - 2015

N2 - © The Author 2015. Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Patients and methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P <0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P <0.001) and activated CD86+CD27+ memory B cells (P

AB - © The Author 2015. Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). Patients and methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P <0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P <0.001) and activated CD86+CD27+ memory B cells (P

U2 - 10.1093/annonc/mdv387

DO - 10.1093/annonc/mdv387

M3 - Article

VL - 26

SP - 2483

EP - 2490

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 12

ER -