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Details

Stereochemistry ACHIRAL
Molecular Formula 2C26H24N8O2.C2H6O
Molecular Weight 1007.1108
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TUCATINIB HEMIETHANOLATE

SMILES

CCO.CC1=C(OC2=CC3=NC=NN3C=C2)C=CC(NC4=NC=NC5=C4C=C(NC6=NC(C)(C)CO6)C=C5)=C1.CC7=C(OC8=CC9=NC=NN9C=C8)C=CC(NC%10=NC=NC%11=C%10C=C(NC%12=NC(C)(C)CO%12)C=C%11)=C7

InChI

InChIKey=UGAFQGGOUGJBMF-UHFFFAOYSA-N
InChI=1S/2C26H24N8O2.C2H6O/c2*1-16-10-17(5-7-22(16)36-19-8-9-34-23(12-19)28-15-30-34)31-24-20-11-18(4-6-21(20)27-14-29-24)32-25-33-26(2,3)13-35-25;1-2-3/h2*4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31);3H,2H2,1H3

HIDE SMILES / InChI

Molecular Formula C26H24N8O2
Molecular Weight 480.5212
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C2H6O
Molecular Weight 46.0684
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

TUCATINIB (ONT-380 or ARRY-380) is an orally active, reversible and selective small-molecule HER2 inhibitor invented by Array and licensed to Cascadian Therapeutics (previously named Oncothyreon) for development, manufacturing and commercialization. HER2, a growth factor receptor that is over-expressed in multiple cancers, including breast, ovarian, and stomach cancer. HER2 mediates cell growth, differentiation and survival, and tumors that overexpress HER2 are more aggressive and historically have been associated with poorer overall survival compared with HER2-negative cancers. ONT-380 is highly active as a single agent and in combination with both chemotherapy and Herceptin® (trastuzumab) in xenograft models of HER2+ breast cancer, including models of CNS metastases that were refractory to Tykerb® (lapatinib) or neratinib treatment. In a Phase 1 single agent clinical study, ONT-380 administered orally twice a day was well tolerated and demonstrated anti-tumor activity in heavily pre-treated HER2+ breast cancer patients with metastatic disease. Based on the strength of these preclinical and clinical trials, ONT-380 is advancing in one Phase 2 and three Phase 1b combination trials in patients with metastatic breast cancer. A second study reported the CNS activity of ONT-380 in combination with either T-DM1 or trastuzumab or capecitabine. Patients with brain metastases assessable for response were included in the combined analysis. Responses and clinical benefit in the CNS were reported with the three combinations tested, supporting future development of the drug for this particular indication.

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
790 ng/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TUCATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
2920 ng × h/mL
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TUCATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
5.5 h
300 mg 2 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TUCATINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
2.9%
TUCATINIB plasma
Homo sapiens
Doses

Doses

DosePopulationAdverse events​
300 mg 2 times / day steady, oral
Recommended
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Co-administed with::
trastuzumab(loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle)
capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle)
Sources:
unhealthy, 54 years (range: 22 - 82 years)
n = 404
Health Status: unhealthy
Age Group: 54 years (range: 22 - 82 years)
Sex: M+F
Population Size: 404
Sources:
Disc. AE: Hepatotoxicity, Diarrhea...
AEs leading to
discontinuation/dose reduction:
Hepatotoxicity (1.5%)
Diarrhea (1%)
Hepatotoxicity (8%)
Diarrhea (6%)
Sources:
800 mg 2 times / day steady, oral
Highest studied dose
Dose: 800 mg, 2 times / day
Route: oral
Route: steady
Dose: 800 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 4
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 4
Sources:
DLT: Alanine aminotransferase increased, Aspartate aminotransferase increased...
Dose limiting toxicities:
Alanine aminotransferase increased (grade 3, 2 patients)
Aspartate aminotransferase increased (grade 3, 2 patients)
Sources:
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Other AEs: Diarrhea, Nausea...
Other AEs:
Diarrhea (grade 1-2, 26%)
Nausea (grade 1-2, 33%)
Fatigue (grade 1-2, 19%)
Vomiting (grade 1-2, 3%)
Acne (grade 3, 4%)
Dermatitis acneiform (grade 3, 4%)
Skin exfoliation (grade 3, 4%)
Alanine aminotransferase increased (grade 3, 4%)
Aspartate aminotransferase increased (grade 2, 11%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Diarrhea 1%
Disc. AE
300 mg 2 times / day steady, oral
Recommended
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Co-administed with::
trastuzumab(loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle)
capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle)
Sources:
unhealthy, 54 years (range: 22 - 82 years)
n = 404
Health Status: unhealthy
Age Group: 54 years (range: 22 - 82 years)
Sex: M+F
Population Size: 404
Sources:
Hepatotoxicity 1.5%
Disc. AE
300 mg 2 times / day steady, oral
Recommended
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Co-administed with::
trastuzumab(loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle)
capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle)
Sources:
unhealthy, 54 years (range: 22 - 82 years)
n = 404
Health Status: unhealthy
Age Group: 54 years (range: 22 - 82 years)
Sex: M+F
Population Size: 404
Sources:
Diarrhea 6%
Disc. AE
300 mg 2 times / day steady, oral
Recommended
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Co-administed with::
trastuzumab(loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle)
capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle)
Sources:
unhealthy, 54 years (range: 22 - 82 years)
n = 404
Health Status: unhealthy
Age Group: 54 years (range: 22 - 82 years)
Sex: M+F
Population Size: 404
Sources:
Hepatotoxicity 8%
Disc. AE
300 mg 2 times / day steady, oral
Recommended
Dose: 300 mg, 2 times / day
Route: oral
Route: steady
Dose: 300 mg, 2 times / day
Co-administed with::
trastuzumab(loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle)
capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle)
Sources:
unhealthy, 54 years (range: 22 - 82 years)
n = 404
Health Status: unhealthy
Age Group: 54 years (range: 22 - 82 years)
Sex: M+F
Population Size: 404
Sources:
Alanine aminotransferase increased grade 3, 2 patients
DLT, Disc. AE
800 mg 2 times / day steady, oral
Highest studied dose
Dose: 800 mg, 2 times / day
Route: oral
Route: steady
Dose: 800 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 4
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 4
Sources:
Aspartate aminotransferase increased grade 3, 2 patients
DLT, Disc. AE
800 mg 2 times / day steady, oral
Highest studied dose
Dose: 800 mg, 2 times / day
Route: oral
Route: steady
Dose: 800 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 4
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 4
Sources:
Fatigue grade 1-2, 19%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Diarrhea grade 1-2, 26%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Vomiting grade 1-2, 3%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Nausea grade 1-2, 33%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Aspartate aminotransferase increased grade 2, 11%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Acne grade 3, 4%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Alanine aminotransferase increased grade 3, 4%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Dermatitis acneiform grade 3, 4%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Skin exfoliation grade 3, 4%
600 mg 2 times / day steady, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: steady
Dose: 600 mg, 2 times / day
Sources:
unhealthy, 58 years (range: 31–77 years)
n = 27
Health Status: unhealthy
Age Group: 58 years (range: 31–77 years)
Sex: M+F
Population Size: 27
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG


OverviewOther

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
yes [IC50 20 uM]
yes (co-administration study)
Comment: Digoxin Cmax increased by 2.4-fold
Page: 81, 83
yes [Ki 0.135 uM]
yes (co-administration study)
Comment: Metformin Cmax increased by 1.1-fold
Page: 81, 83
yes [Ki 0.17 uM]
yes (co-administration study)
Comment: Repaglinide Cmax increased by 1.7-fold
Page: 80, 83
yes [Ki 0.34 uM]
yes (co-administration study)
Comment: Metformin Cmax increased by 1.1-fold
Page: 81, 83
yes [Ki 0.805 uM]
yes (co-administration study)
Comment: Midazolam Cmax increased by 3-fold
Page: 80, 83
yes [Ki 14.7 uM]
yes [Ki 4.57 uM]
no (co-administration study)
Comment: No effect on tolbutamide Cmax or AUC
Page: 80, 83
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
yes
yes
yes
weak (co-administration study)
Comment: Itraconazole increased tucatinib Cmax by 1.3-fold; Rifampin decreased tucatinib Cmax by 37%
Page: 80, 83
yes
yes (co-administration study)
Comment: Gemfibrozil increased tucatinib Cmax by 1.6-fold; Rifampin decreased tucatinib Cmax by 37%
Page: 80, 83
Tox targets

Tox targets

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2(+)-Advanced Solid Tumors, with an Expansion Cohort in HER2(+) Metastatic Breast Cancer (MBC).
2017 Jul 15
Patents

Sample Use Guides

Phase 2 Study of tucatinib in combination with capecitabine & trastuzumab in patients with advanced HER2+ breast cancer: Tucatinib 300 mg or placebo will be given orally twice daily (PO BID).
Route of Administration: Oral
In Vitro Use Guide
Unknown
Substance Class Chemical
Created
by admin
on Sat Dec 16 18:07:32 UTC 2023
Edited
by admin
on Sat Dec 16 18:07:32 UTC 2023
Record UNII
CDZ29KT2FT
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TUCATINIB HEMIETHANOLATE
Common Name English
ETHANOL, COMPD. WITH N6-(4,5-DIHYDRO-4,4-DIMETHYL-2-OXAZOLYL)-N4-(3-METHYL-4-((1,2,4)TRIAZOLO(1,5-A)PYRIDIN-7-YLOXY)PHENYL)-4,6-QUINAZOLINEDIAMINE (1:2)
Systematic Name English
Code System Code Type Description
FDA UNII
CDZ29KT2FT
Created by admin on Sat Dec 16 18:07:32 UTC 2023 , Edited by admin on Sat Dec 16 18:07:32 UTC 2023
PRIMARY
CAS
1429755-56-5
Created by admin on Sat Dec 16 18:07:32 UTC 2023 , Edited by admin on Sat Dec 16 18:07:32 UTC 2023
PRIMARY
SMS_ID
300000024838
Created by admin on Sat Dec 16 18:07:32 UTC 2023 , Edited by admin on Sat Dec 16 18:07:32 UTC 2023
PRIMARY
PUBCHEM
162623678
Created by admin on Sat Dec 16 18:07:32 UTC 2023 , Edited by admin on Sat Dec 16 18:07:32 UTC 2023
PRIMARY
Related Record Type Details
ANHYDROUS->SOLVATE
PARENT -> SALT/SOLVATE
Related Record Type Details
ACTIVE MOIETY