Tesetaxel

Tesetaxel
Clinical data
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C46H60FN3O13
Molar mass 881.98 g/mol
3D model (JSmol)
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Tesetaxel is an orally administered taxane being investigated as a chemotherapy agent for various types of cancer, including breast cancer,[1] gastric cancer,[2] colorectal cancer,[3] and other solid tumors.[4] It differs from other members of the taxane class (e.g. paclitaxel or docetaxel) in that it is administered orally, not intravenously.[5]

Preclinical studies

The first preclinical studies for tesetaxel were carried out prior to 2003 both in vitro and in vivo.[5] In both in vitro and in vivo efficacy studies, tesetaxel exhibited stronger cytotoxicity than paclitaxel and docetaxel against various tumor cell lines, especially against P-glycoprotein (P-gp)-expressing tumor cells.[5][6]

In vitro, tesetaxel’s average growth inhibition of 50% (GI50) showed that it was about 20 times more effective than paclitaxel and 5 times more effective than docetaxel in 6 human tumor cell lines expressing P-glycoprotein (P-gp).[5] In 6 different P-gp positive human tumor cell lines with drug-induced resistance, tesetaxel exhibited a 10- to 100-fold greater cytotoxicity than paclitaxel and docetaxel.[5]

In vivo, tesetaxel exhibited significant growth-inhibitory effects (IR>90%) on P-gp-positive colon cancer DLD-1 and breast cancer DU4475 xenografts, on which neither docetaxel nor paclitaxel was effective (their IR values ranged from 26% to 58%).[5]

Clinical studies

Odonate Therapeutics, Inc. is conducting an approximately 600-patient, multinational, multicenter, randomized, open-label, parallel Phase 3 study, known as CONTESSA that will compare tesetaxel (27 mg/m² on the first day of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m²/day on days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m²/day on days 1-14 of a 21-day cycle) in patients with human epidermal growth factor receptor 2 (HER2) negative, hormone receptor (HR) positive locally advanced metastatic breast cancer (MBC) previously treated with a taxane in the neoadjuvant (prior to surgery) or adjuvant (immediately following surgery) setting.[7] CONTESSA’s primary endpoint is progression-free survival (PFS). CONTESSA’s secondary endpoints are overall survival (OS), objective response rate (ORR), disease control rate (DCR) and patient reported outcomes (PROs).[7]

References

  1. ↑ Clinical trial number NCT01221870 for "Tesetaxel as First-line Therapy for Metastatic Breast Cancer" at ClinicalTrials.gov
  2. ↑ Evans, T.; Dobrila, R.; Berardi, R.; Sumpter, K.A.; Wall, L.R.; Oyama, R. (June 2006). "A phase II study of DJ-927 as second-line therapy in patients (pts) with advanced gastric cancer (GC) who have failed a 5-FU non taxane based regimen". Journal of Clinical Oncology.
  3. ↑ Clinical trial number NCT00080834 for "DJ-927 as Second-Line Therapy in Treating Patients With Progressive Locally Advanced or Metastatic Colorectal Adenocarcinoma" at ClinicalTrials.gov
  4. ↑ Clinical trial number NCT01315431 for "A Study of Tesetaxel Plus Capecitabine in Patients With Solid Tumors" at ClinicalTrials.gov
  5. 1 2 3 4 5 6 Shionoya, Motoko; Jimbo, Takeshi; Kitagawa, Mayumi; Soga, Tsunehiko; Tohgo, Akiko (2003). "DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo". Cancer Science. 94 (5): 459–466. doi:10.1111/j.1349-7006.2003.tb01465.x.
  6. ↑ Yared, Jean A.; Tcakzul, Katherine HR (2012). "Update on taxane development: new analogs and new formulations". Drug Design, Development and Therapy. 6: 371–384. doi:10.2147/DDDT.S28997.
  7. 1 2 Clinical trial number NCT03326674 for "Tesetaxel Plus Reduced Dose of Capecitabine vs. Capecitabine in HER2 Negative, HR Positive, MBC (CONTESSA) (CONTESSA)" at ClinicalTrials.gov
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