PMID- 34515215
OWN - NLM
STAT- MEDLINE
DCOM- 20211015
LR  - 20211015
IS  - 2296-5262 (Electronic)
IS  - 2296-5270 (Linking)
VI  - 44
IP  - 10
DP  - 2021
TI  - A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with 
      Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse 
      Events.
PG  - 547-556
LID - 10.1159/000518549 [doi]
AB  - PURPOSE: This first-in-human study (NCT02947152) evaluated the safety, 
      tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a 
      first-in-class CDH6-targeting antibody-drug conjugate (ADC). EXPERIMENTAL DESIGN: 
      HKT288 was administered intravenously (IV) every 3 weeks until patients 
      experienced unacceptable toxicity or progressive disease (PD). The starting dose 
      of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in 
      monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, 
      eyes, bone marrow, and liver were expected targets of toxicity. RESULTS: Nine 
      patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian 
      cancer. The best overall response on the 0.3 mg/kg cohort in patients with 
      measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 
      patients. The most frequent adverse events (AEs) regardless of causality were 
      pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). 
      Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg 
      cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. 
      Further studies were unable to identify the underlying mechanism of the 
      neurologic AEs, and the study was terminated early. CONCLUSIONS: Preclinical 
      toxicology did not predict the neurotoxicity observed with HKT288, and a 
      comprehensive assessment performed post hoc did not identify the mechanism of 
      toxicity. The development of further CDH6-targeting ADCs should be pursued with 
      caution.
CI  - (c) 2021 S. Karger AG, Basel.
FAU - Schoffski, Patrick
AU  - Schoffski P
AD  - Department of General Medical Oncology, University Hospitals Leuven, Leuven, 
      Belgium.
AD  - Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
FAU - Concin, Nicole
AU  - Concin N
AD  - Department of Gynecology and Obstetrics, Medical University Innsbruck, Innsbruck, 
      Austria.
FAU - Suarez, Cristina
AU  - Suarez C
AD  - Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), 
      Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, 
      Barcelona, Spain.
FAU - Subbiah, Vivek
AU  - Subbiah V
AD  - Department of Investigational Cancer Therapeutics, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
FAU - Ando, Yuichi
AU  - Ando Y
AD  - Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 
      Nagoya, Japan.
FAU - Ruan, Shiling
AU  - Ruan S
AD  - Clinical Development & Analytics, Novartis Pharmaceuticals Corporation, East 
      Hanover, New Jersey, USA.
FAU - Wagner, Joel P
AU  - Wagner JP
AD  - Oncology Data Science, Novartis Institutes for BioMedical Research (NIBR), 
      Cambridge, Massachusetts, USA.
FAU - Mansfield, Keith
AU  - Mansfield K
AD  - Preclinical Safety, Novartis Institutes for BioMedical Research (NIBR), 
      Cambridge, Massachusetts, USA.
FAU - Zhu, Xu
AU  - Zhu X
AD  - PK Sciences, Novartis Institutes for BioMedical Research (NIBR), Cambridge, 
      Massachusetts, USA.
FAU - Origuchi, Shizuka
AU  - Origuchi S
AD  - Translational Clinical Oncology, Novartis Institutes for BioMedical Research 
      (NIBR), Cambridge, Massachusetts, USA.
FAU - DiDominick, Sarah
AU  - DiDominick S
AD  - Translational Clinical Oncology, Novartis Institutes for BioMedical Research 
      (NIBR), Cambridge, Massachusetts, USA.
FAU - Bialucha, Carl U
AU  - Bialucha CU
AD  - Oncology Research, Biotherapeutics, Novartis Institutes for BioMedical Research 
      (NIBR), Cambridge, Massachusetts, USA.
FAU - Faris, Jason E
AU  - Faris JE
AD  - Translational Clinical Oncology, Novartis Institutes for BioMedical Research 
      (NIBR), Cambridge, Massachusetts, USA.
FAU - Tran, Ben
AU  - Tran B
AD  - Department of Medical Oncology, Peter Maccallum Cancer Centre, Melbourne, 
      Victoria, Australia.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20210819
PL  - Switzerland
TA  - Oncol Res Treat
JT  - Oncology research and treatment
JID - 101627692
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunoconjugates)
SB  - IM
MH  - *Antineoplastic Agents/adverse effects
MH  - *Carcinoma, Renal Cell
MH  - Female
MH  - Humans
MH  - *Immunoconjugates/adverse effects
MH  - *Kidney Neoplasms/drug therapy
MH  - *Neoplasms/drug therapy
MH  - *Ovarian Neoplasms/drug therapy
OTO - NOTNLM
OT  - Advanced solid tumors
OT  - Cadherin-6
OT  - HKT288
OT  - Neurological toxicity
OT  - Phase 1
EDAT- 2021/09/14 06:00
MHDA- 2021/10/16 06:00
CRDT- 2021/09/13 09:25
PHST- 2021/04/01 00:00 [received]
PHST- 2021/07/16 00:00 [accepted]
PHST- 2021/09/14 06:00 [pubmed]
PHST- 2021/10/16 06:00 [medline]
PHST- 2021/09/13 09:25 [entrez]
AID - 000518549 [pii]
AID - 10.1159/000518549 [doi]
PST - ppublish
SO  - Oncol Res Treat. 2021;44(10):547-556. doi: 10.1159/000518549. Epub 2021 Aug 19.