Population PK and Exposure-Response Relationships for the Antibody-Drug Conjugate Brentuximab Vedotin in CTCL Patients in the Phase III ALCANZA Study

Ajit Suri; Diane R Mould; Yi Liu; Graham Jang; Karthik Venkatakrishnan

doi:10.1002/cpt.1037

Population PK and Exposure-Response Relationships for the Antibody-Drug Conjugate Brentuximab Vedotin in CTCL Patients in the Phase III ALCANZA Study

Clin Pharmacol Ther. 2018 Nov;104(5):989-999. doi: 10.1002/cpt.1037. Epub 2018 Feb 23.

Authors

Ajit Suri¹, Diane R Mould², Yi Liu¹, Graham Jang³, Karthik Venkatakrishnan¹

Affiliations

¹ Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts, USA.
² Projections Research, Inc., Phoenixville, Pennsylvania, USA.
³ Seattle Genetics, Inc., Bothell, Washington, USA.

Abstract

The antibody-drug conjugate (ADC) brentuximab vedotin consists of the CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In pharmacokinetic models, including data from six studies (380 patients with classical Hodgkin's, systemic anaplastic large-cell, and cutaneous T-cell (CTCL) lymphomas), lower clearance of ADC and modestly higher ADC exposure in CTCL patients did not translate into higher MMAE exposure. In CTCL patients from the phase III ALCANZA study (n = 66), improved progression-free survival with brentuximab vedotin vs. controls was not related to ADC exposure. ADC exposure was a predictor of grade ≥3 treatment-emergent adverse events (TEAEs). Results support the consistent benefit observed with brentuximab vedotin 1.8 mg/kg every 3 weeks across the range of exposures in ALCANZA and support dose reductions in patients experiencing TEAEs at the starting dose.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Immunological / administration & dosage
Antineoplastic Agents, Immunological / adverse effects
Antineoplastic Agents, Immunological / blood
Antineoplastic Agents, Immunological / pharmacokinetics*
Brentuximab Vedotin
Child
Clinical Trials, Phase III as Topic
Computer Simulation
Dose-Response Relationship, Drug
Drug Administration Schedule
Drug Dosage Calculations
Drug Monitoring
Female
Humans
Immunoconjugates / administration & dosage
Immunoconjugates / adverse effects
Immunoconjugates / blood
Immunoconjugates / pharmacokinetics*
Lymphoma, T-Cell, Cutaneous / blood
Lymphoma, T-Cell, Cutaneous / diagnosis
Lymphoma, T-Cell, Cutaneous / drug therapy*
Lymphoma, T-Cell, Cutaneous / immunology
Male
Middle Aged
Models, Biological*
Progression-Free Survival
Risk Assessment
Skin Neoplasms / blood
Skin Neoplasms / diagnosis
Skin Neoplasms / drug therapy*
Skin Neoplasms / immunology
Young Adult

Substances

Antineoplastic Agents, Immunological
Immunoconjugates
Brentuximab Vedotin