PMID- 34045233
OWN - NLM
STAT- MEDLINE
DCOM- 20220219
LR  - 20240229
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 20
IP  - 8
DP  - 2021 Aug
TI  - First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 
      Antibody-Drug Conjugate MEDI4276 in Patients with HER2-positive Advanced Breast 
      or Gastric Cancer.
PG  - 1442-1453
LID - 10.1158/1535-7163.MCT-20-0014 [doi]
AB  - MEDI4276 is a biparatopic tetravalent antibody targeting two nonoverlapping 
      epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific 
      conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 
      demonstrates enhanced cellular internalization and cytolysis of HER2-positive 
      tumor cells in vitro This was a first-in-human, dose-escalation clinical trial in 
      patients with HER2-positive advanced or metastatic breast cancer or gastric 
      cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute 
      intravenous infusion every 3 weeks). Primary endpoints were safety and 
      tolerability; secondary endpoints included antitumor activity (objective 
      response, progression-free survival, and overall survival), pharmacokinetics, and 
      immunogenicity. Forty-seven patients (median age 59 years; median of seven prior 
      treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 
      mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 
      liver function test (LFT) increases, one of whom also had grade 3 diarrhea, which 
      resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower 
      doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse 
      events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase 
      (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 
      drug-related AE was AST increased (21.3%). Five patients had drug-related AEs 
      leading to treatment discontinuation. In the as-treated population, there was one 
      complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 
      0.75 mg/kg; breast cancer)-all had prior trastuzumab, pertuzumab, and 
      ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity 
      but displays intolerable toxicity at doses >0.3 mg/kg.
CI  - (c)2021 The Authors; Published by the American Association for Cancer Research.
FAU - Pegram, Mark D
AU  - Pegram MD
AUID- ORCID: 0000-0002-9743-8118
AD  - Stanford Comprehensive Cancer Institute, Stanford, California. 
      mpegram@stanford.edu.
FAU - Hamilton, Erika P
AU  - Hamilton EP
AD  - Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
FAU - Tan, Antoinette R
AU  - Tan AR
AUID- ORCID: 0000-0002-7895-7000
AD  - Levine Cancer Institute, Atrium Health, Charlotte, North Carolina.
FAU - Storniolo, Anna Maria
AU  - Storniolo AM
AD  - Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, 
      Indianapolis, Indiana.
FAU - Balic, Kemal
AU  - Balic K
AD  - AstraZeneca, South San Francisco, California.
FAU - Rosenbaum, Anton I
AU  - Rosenbaum AI
AUID- ORCID: 0000-0003-1939-951X
AD  - AstraZeneca, South San Francisco, California.
FAU - Liang, Meina
AU  - Liang M
AD  - AstraZeneca, South San Francisco, California.
FAU - He, Peng
AU  - He P
AD  - AstraZeneca, Gaithersburg, Maryland.
FAU - Marshall, Shannon
AU  - Marshall S
AD  - AstraZeneca, Gaithersburg, Maryland.
FAU - Scheuber, Anita
AU  - Scheuber A
AD  - Boston Pharmaceuticals, Cambridge, Massachusetts.
FAU - Das, Mayukh
AU  - Das M
AD  - AstraZeneca, Gaithersburg, Maryland.
FAU - Patel, Manish R
AU  - Patel MR
AUID- ORCID: 0000-0001-6836-2364
AD  - Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20210527
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Immunoconjugates)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - 0 (MEDI4276)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Antibodies, Monoclonal/chemistry
MH  - *Antineoplastic Agents, Immunological/chemistry/pharmacokinetics/pharmacology
MH  - *Breast Neoplasms/drug therapy/immunology/metabolism/pathology
MH  - Follow-Up Studies
MH  - *Immunoconjugates/chemistry/pharmacokinetics/pharmacology
MH  - Maximum Tolerated Dose
MH  - Prognosis
MH  - *Receptor, ErbB-2/immunology
MH  - *Stomach Neoplasms/drug therapy/immunology/metabolism/pathology
MH  - Survival Rate
MH  - Tissue Distribution
PMC - PMC9398097
EDAT- 2021/05/29 06:00
MHDA- 2022/02/19 06:00
PMCR- 2022/08/23
CRDT- 2021/05/28 06:27
PHST- 2020/10/13 00:00 [received]
PHST- 2021/03/04 00:00 [revised]
PHST- 2021/05/25 00:00 [accepted]
PHST- 2021/05/29 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/05/28 06:27 [entrez]
PHST- 2022/08/23 00:00 [pmc-release]
AID - 1535-7163.MCT-20-0014 [pii]
AID - MCT-20-0014 [pii]
AID - 10.1158/1535-7163.MCT-20-0014 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2021 Aug;20(8):1442-1453. doi: 10.1158/1535-7163.MCT-20-0014. 
      Epub 2021 May 27.