Details
Stereochemistry | ACHIRAL |
Molecular Formula | C26H24N8O2 |
Molecular Weight | 480.5212 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1=C(OC2=CC3=NC=NN3C=C2)C=CC(NC4=NC=NC5=C4C=C(NC6=NC(C)(C)CO6)C=C5)=C1
InChI
InChIKey=SDEAXTCZPQIFQM-UHFFFAOYSA-N
InChI=1S/C26H24N8O2/c1-16-10-17(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/h4-12,14-15H,13H2,1-3H3,(H,32,33)(H,27,29,31)
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.
CNS Activity
Approval Year
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
790 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29955792 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2920 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29955792 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29955792 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.9% |
TUCATINIB plasma | Homo sapiens |
Doses
Dose | Population | Adverse 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) Sources: capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle) |
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%) Sources: Diarrhea (1%) Hepatotoxicity (8%) Diarrhea (6%) |
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) Sources: Aspartate aminotransferase increased (grade 3, 2 patients) |
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%) Sources: 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%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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) Sources: capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle) |
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) Sources: capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle) |
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) Sources: capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle) |
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) Sources: capecitabine(1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle) |
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
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Drug as victim
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/213411Orig1s000MultidisciplineR.pdf Page: 39.0 |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT02614794
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
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Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C2167
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FDA ORPHAN DRUG |
570716
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FDA ORPHAN DRUG |
603217
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FDA ORPHAN DRUG |
571216
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Tucatinib
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CHEMBL3545380
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9997
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DE-115
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937263-43-9
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C77896
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5389
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DTXSID601027958
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SUB177913
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234248D0HH
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2361285
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m12198
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100000163588
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234248D0HH
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51039094
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DB11652
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Tucatinib
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)