A Phase Ib/II study of IGF-neutralising antibody xentuzumab with enzalutamide in metastatic castration-resistant prostate cancer

Background This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC). Methods The trial included Phase Ib escalation and expansion parts and a randomis...

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Bibliographic Details
Published in:British journal of cancer Vol. 129; no. 6; pp. 965 - 973
Main Authors: Macaulay, Valentine M., Lord, Simon, Hussain, Syed, Maroto, José Pablo, Jones, Robert Hugh, Climent, Miguel Ángel, Cook, Natalie, Lin, Chia-Chi, Wang, Shian-Shiang, Bianchini, Diletta, Bailey, Mark, Schlieker, Laura, Bogenrieder, Thomas, de Bono, Johann
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 05.10.2023
Nature Publishing Group
Subjects:
631/154
631/67/589/466
692/4028/67/589/466
Antibodies, Neutralizing
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Biomedical and Life Sciences
Biomedicine
Cancer Research
Castration
Drug Resistance
Epidemiology
Humans
Insulin-like growth factor I
Insulin-like growth factors
Male
Metastases
Metastasis
Molecular Medicine
mRNA
Nitriles - therapeutic use
Oncology
Prostate cancer
Prostate-specific antigen
Prostatic Neoplasms, Castration-Resistant - pathology
PTEN protein
Treatment Outcome
ISSN:0007-0920, 1532-1827, 1532-1827
Online Access:Get full text
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Summary:Background This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC). Methods The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone. Results In the Phase Ib escalation ( n  = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion ( n  = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II ( n  = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated. Conclusions Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC. Clinical trial registration EudraCT number 2013-004011-41.
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-023-02380-1