PMID- 27178743
OWN - NLM
STAT- MEDLINE
DCOM- 20180131
LR  - 20220331
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 22
IP  - 20
DP  - 2016 Oct 15
TI  - Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug 
      Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal 
      Malignancies.
PG  - 5049-5057
AB  - PURPOSE: To assess the safety, tolerability, and preliminary antitumor activity 
      of the investigational anti-guanylyl cyclase C (GCC) antibody-drug conjugate 
      TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal 
      malignancies. EXPERIMENTAL DESIGN: Adult patients with GCC-expressing 
      gastrointestinal malignancies (H-score >/= 10) were eligible for inclusion. TAK-264 
      was administered as a 30-minute intravenous infusion once every 3 weeks for up to 
      17 cycles. Dose escalation proceeded using a Bayesian continual reassessment 
      method. At the maximum tolerated dose (MTD), 25 patients with metastatic 
      colorectal cancer were enrolled in a prespecified dose expansion cohort. RESULTS: 
      Forty-one patients were enrolled, including 35 (85%) with metastatic colorectal 
      cancer. During dose escalation (0.3-2.4 mg/kg), four of 19 patients experienced 
      dose-limiting toxicities of grade 4 neutropenia; the MTD was determined as 1.8 
      mg/kg. Patients received a median of two cycles of TAK-264 (range, 1-12); nine 
      received >/=four cycles. Common drug-related adverse events (AEs) included nausea 
      and decreased appetite (each 41%), fatigue (32%), diarrhea, anemia, alopecia, and 
      neutropenia (each 27%); grade >/=3 AEs included neutropenia (22%), hypokalemia, and 
      febrile neutropenia (each 7%). Peripheral neuropathy was reported in four (10%) 
      patients. Pharmacokinetic data showed approximately dose proportional systemic 
      exposure and a mean plasma half-life of around 4 days, supporting the dosing 
      schedule. Overall, 39 patients were response-evaluable; three experienced durable 
      stable disease; and one with gastric adenocarcinoma had a partial response. GCC 
      expression did not appear to correlate with treatment duration. CONCLUSIONS: 
      These findings suggest that TAK-264 has a manageable safety profile, with 
      preliminary evidence of potential antitumor activity in specific gastrointestinal 
      malignancies. Further investigation is underway. Clin Cancer Res; 22(20); 
      5049-57. (c)2016 AACR.
CI  - (c)2016 American Association for Cancer Research.
FAU - Almhanna, Khaldoun
AU  - Almhanna K
AD  - Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida. 
      Khaldoun.Almhanna@moffitt.org.
FAU - Kalebic, Thea
AU  - Kalebic T
AD  - Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, Massachusetts.
FAU - Cruz, Cristina
AU  - Cruz C
AD  - Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital and 
      Universitat Autonoma de Barcelona, Barcelona, Spain.
FAU - Faris, Jason E
AU  - Faris JE
AD  - Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, 
      Massachusetts.
FAU - Ryan, David P
AU  - Ryan DP
AD  - Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, 
      Massachusetts.
FAU - Jung, JungAh
AU  - Jung J
AD  - Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, Massachusetts.
FAU - Wyant, Tim
AU  - Wyant T
AD  - Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, Massachusetts.
FAU - Fasanmade, Adedigbo A
AU  - Fasanmade AA
AD  - Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
      Pharmaceutical Company Limited, Cambridge, Massachusetts.
FAU - Messersmith, Wells
AU  - Messersmith W
AD  - Division of Medical Oncology, University of Colorado Cancer Center, Aurora, 
      Colorado.
FAU - Rodon, Jordi
AU  - Rodon J
AD  - Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital and 
      Universitat Autonoma de Barcelona, Barcelona, Spain.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
DEP - 20160513
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunoconjugates)
RN  - 0 (Oligopeptides)
RN  - EC 4.6.1.2 (Guanylate Cyclase)
RN  - V7I58RC5EJ (monomethyl auristatin E)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/pathology
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/adverse effects/therapeutic use
MH  - Antineoplastic Agents/adverse effects/*therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gastrointestinal Neoplasms/*drug therapy/pathology
MH  - Guanylate Cyclase/*antagonists & inhibitors/immunology
MH  - Humans
MH  - Immunoconjugates/adverse effects/*therapeutic use
MH  - Male
MH  - *Maximum Tolerated Dose
MH  - Middle Aged
MH  - Oligopeptides/adverse effects/therapeutic use
EDAT- 2016/05/15 06:00
MHDA- 2018/02/01 06:00
CRDT- 2016/05/15 06:00
PHST- 2015/10/12 00:00 [received]
PHST- 2016/04/18 00:00 [accepted]
PHST- 2016/05/15 06:00 [pubmed]
PHST- 2018/02/01 06:00 [medline]
PHST- 2016/05/15 06:00 [entrez]
AID - 1078-0432.CCR-15-2474 [pii]
AID - 10.1158/1078-0432.CCR-15-2474 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2016 Oct 15;22(20):5049-5057. doi: 
      10.1158/1078-0432.CCR-15-2474. Epub 2016 May 13.