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Accelerating drug development by efficiently using emerging PK/PD data from an adaptable entry-into-human trial: example of lumretuzumab.

Abstract：

PURPOSE:This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. METHODS:Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens. RESULTS:The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400-2000 mg q2w in combination regimens were consistent with the model predictions. CONCLUSION:PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Meneses-Lorente G,McIntyre C,Hsu JC,Thomas M,Jacob W,Adessi C,Weisser M

doi

10.1007/s00280-017-3328-3

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

1239-1247

issue

6

eissn

0344-5704

issn

1432-0843

pii

10.1007/s00280-017-3328-3

journal_volume

79

pub_type

杂志文章,多中心研究

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