Abstract
The taxanes paclitaxel, docetaxel and cabazitaxel are important anticancer agents that are widely used as intravenous treatment for several solid tumor types. Switching from intravenous to oral treatment can be more convenient for patients, improve cost–effectiveness and reduce the demands of chemotherapy treatment on hospital care. However, oral treatment with taxanes is challenging because of pharmaceutical and pharmacological factors that lead to low oral bioavailability. This review summarizes the current clinical developments in oral taxane treatment. Intravenous parent drugs, strategies in the oral switch, individual agents in clinical trials, challenges and further perspectives on treatment with oral taxanes are subsequently discussed.
Papers of special note have been highlighted as: •• of considerable interest
References
- 1. Prospects for combining targeted and conventional therapy with immunotherapy. Nat. Rev. Cancer 17(5), 286–301 (2017).
- 2. . Palliative chemotherapy: no longer a contradiction in terms. Oncologist 4(6), 470–477 (1999).
- 3. . Patient preference for oral versus intravenous palliative chemotherapy. J. Clin. Oncol. 15(1), 110–115 (1997).
- 4. . Answering patient's needs: oral alternatives to intravenous therapy. Oncologist 6(Suppl. 4), 12–16 (2001).
- 5. Comparative cost-minimisation of oral and intravenous chemotherapy for first-line treatment of non-small cell lung cancer in the UK NHS system. Eur. J. Health Econ. 8(2), 145–151 (2007).
- 6. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes C colon cancer: the X-ACT trial. Br. J. Cancer 94(8), 1122–1129 (2006).
- 7. Caring for patients with cancer in the COVID-19 area. Nat. Med. 26, 665–671 (2020).
- 8. . Clinical pharmacology of anticancer agents in relation to formulations and administration routes. Cancer Treat. Rev. 25(2), 83–101 (1999).
- 9. Randomized Phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J. Clin. Oncol. 26(10), 1642–1649 (2008).
- 10. . The pharmacological bases of antiangiogenic activity of paclitaxel. Angiogenesis 16, 481–492 (2013).
- 11. . Novel formulations of taxanes: a review. Old wine in a new bottle? Ann. Oncol. 17(5), 735–749 (2006).
- 12. Anticancer oral therapy: emerging related issues. Cancer Treat. Rev. 36(8), 595–605 (2010). •• Describes the advantages and challenges of oral anticancer treatment.
- 13. . Oral cancer treatment: developments in chemotherapy and beyond. Br. J. Cancer 87(9), 933–937 (2002).
- 14. Patient experiences with oral chemotherapy: adherence, symptoms and quality of life. J. Natl Compr. Canc. Netw. 17(3), 221–228 (2019).
- 15. Advancements in the oral delivery of docetaxel: challenges, current state-of-the-art and future trends. Int. J. Nanomedicine 13, 3145–3161 (2018).
- 16. . Novel oral taxane therapies: recent Phase I results. Clin. Investig. (Lond.) 3(4), 333–341 (2013).
- 17. . Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93, 2325–2327 (1971).
- 18. . Taxol: a new and effective anti-cancer drug. Anticancer Drugs 2(6), 519–530 (1991).
- 19. . Chemotherapy in advanced ovarian carcinoma: current standards of care based on randomized trials. Gynecol. Oncol. 55(3 Pt 2), S97–S107 (1994).
- 20. . Paclitaxel (taxol)/carboplatin combination therapy in the treatment of advanced ovarian cancer. Semin. Oncol. 27(3 Suppl. 7), 3–7 (2000).
- 21. . The emerging role of paclitaxel in breast cancer therapy. Clin. Cancer Res. 1(3), 247–256 (1995).
- 22. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J. Clin. Oncol. 26(12), 1980–1986 (2008).
- 23. . Breast cancer: weekly paclitaxel – still preferred first-line taxane for mBC. Nat. Rev. Clin. Oncol. 12(9), 508–509 (2015).
- 24. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analysis of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379(9814), 432–444 (2012).
- 25. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N. Engl. J. Med. 372(2), 134–141 (2015).
- 26. Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J. Clin. Oncol. 16(6), 2133–2141 (1998).
- 27. . The biology and management of non-small cell lung cancer. Nature 533(7689), 446–454 (2018).
- 28. . Systemic treatment of AIDS-related Kaposi sarcoma: current status and perspectives. Cancer Treat. Rev. 32(6), 445–455 (2006).
- 29. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 95(1), 147–154 (2002).
- 30. . Paclitaxel chemotherapy for the treatment of gastric cancer. Gastric Cancer 12, 69–78 (2009).
- 31. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised Phase 3 trial. Lancet Oncol. 15(11), 1224–1235 (2014).
- 32. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann. Oncol. 30(1), 19–33 (2019).
- 33. . A highly efficient, practical approach to natural taxol. J. Am. Chem. Soc. 110(17), 5917–5919 (1988).
- 34. . Docetaxel (taxotere): single agent activity, development of combination treatment and reducing side effects. Cancer Treat. Rev. 21(5), 463–478 (1995).
- 35. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351(15), 1502–1512 (2014).
- 36. Taxane-based chemohormonal therapy for metastatic hormone-sensitive prostate cancer. Cochrane Database Syst. Rev. 10, CD012816 (2018).
- 37. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J. Clin. Oncol. 17(5), 1413–1424 (1999).
- 38. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised Phase III study with crossover on progression by the Scandinavian Breast Group. Eur. J. Cancer 35(8), 1194–1201 (1999).
- 39. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J. Clin. Oncol. 20(12), 2812–2823 (2002).
- 40. Pertuzumab, trastuzumab and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomized, double-blind, placebo-controlled, Phase 3 study. Lancet Oncol. 14(6), 461–471 (2013).
- 41. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the Phase 3 randomised BCIRG 001 trial. Lancet Oncol. 14(1), 72–80 (2013).
- 42. . Taxanes for adjuvant treatment of early breast cancer. Cochrane Database Syst. Rev. 9, CD004421 (2019).
- 43. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J. Clin. Oncol. 18(10), 2095–2103 (2000).
- 44. Randomized Phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J. Clin. Oncol. 18(12), 2354–2362 (2000).
- 45. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann. Oncol. 29(4), 959–965 (2018).
- 46. . Docetaxel in the management of head and neck cancer. Anticancer Drugs 20(8), 639–645 (2009).
- 47. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised Phase 3 trial. Lancet Oncol. 12(2), 153–159 (2011).
- 48. . Docetaxel in the treatment of gastric cancer. Future Oncol. 2(5), 603–620 (2006).
- 49. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J. Clin. Oncol. 24(31), 4991–4997 (2006).
- 50. Chemotherapy for advanced gastric cancer. Cochrane Database Syst. Rev. 8, CD004064 (2017).
- 51. . Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer? Clin. Cancer Res. 18(24), 6574–6579 (2012).
- 52. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376(9747), 1147–1154 (2010).
- 53. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized Phase III trial – FIRSTANA. J. Clin. Oncol. 35(28), 3189–3197 (2017).
- 54. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer – PROSELICA. J. Clin. Oncol. 35(28), 3198–3206 (2017).
- 55. A multicenter Phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann. Oncol. 19(9), 1547–1552 (2008).
- 56. A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a Phase I/II study. Eur. J. Cancer 47(7), 1037–1045 (2011).
- 57. . P-glycoprotein and cytochrome P450 3A4 act together in restricting the oral bioavailability of paclitaxel. Int. J. Cancer 132(10), 2439–2447 (2013).
- 58. Absence of both cytochrome P450 3A and P-glycoprotein dramatically increases docetaxel oral bioavailability and risk of intestinal toxicity. Cancer Res. 69(23), 8996–9002 (2009).
- 59. Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int. J. Cancer 136(1), 225–233 (2015).
- 60. . Individual and combined roles of CYP3A, P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) in the pharmacokinetics of docetaxel. Int. J. Cancer 127, 2959–2964 (2010).
- 61. . Regioselective metabolism of toxoids by human CYP3A4 and 2C8: structure–activity relationship. Drug Metab. Dispos. 30(4), 438–445 (2002).
- 62. . The battle of ‘nano’ paclitaxel. Adv. Drug Deliv. Rev. 122, 20–30 (2017).
- 63. . Pharmacokinetics, safety and early activity of a nanoparticle micellar formulation of docetaxel in women with metastatic breast cancer: results from two randomized trials (Phase I and II). 2020 ASCO Virtual Scientific Program. J. Clin. Oncol. 38(15), 3526 (2020).
- 64. Intratumoral comparison of nanoparticle entrapped docetaxel (CPC634) with conventional docetaxel in patients with solid tumours. Clin. Cancer Res. 26(14), 3537–3545 (2020).
- 65. A Phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. Cancer Chemother. Pharmacol. 71(3), 627–633 (2013).
- 66. Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 74(6), 1241–1250 (2014).
- 67. Enhanced absorption and tissue distribution of paclitaxel following oral administration of DHP107, a novel mucoadhesive lipid dosage form. Cancer Chemother. Pharmacol. 64(1), 87–94 (2009).
- 68. A Phase I/IIa study of DHP107, a novel oral paclitaxel formulation, in patients with advanced solid tumors or gastric cancer. Oncologist 22(2), 129–e8 (2017).
- 69. Efficacy and safety findings from DREAM: a Phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann. Oncol. 29(5), 1120–1126 (2018). •• Led to marketing authorization (in Korea) of liporaxel as first oral taxane worldwide.
- 70. Phase 2 study of DHP107 (liporaxel, oral paclitaxel) in first-line, HER2 negative recurrent/metastatic breast cancer (OPTIMAL study, NCT03315364). Ann. Oncol. 30(Suppl. 5), v104–v142 (2019).
- 71. OPTIMAL 3: a Phase III trial to evaluate the efficacy and safety of DHP107 (liporaxel, oral paclitaxel) compared to Taxol (IV paclitaxel) as first line therapy in patients with recurrent or metastatic HER2 negative breast cancer (BC) (NCT03315364). J. Clin. Oncol. 38(Suppl. 15), TPS1106 (2020).
- 72. A Phase II study to evaluate the efficacy, safety and pharmacokinetics of DHP107 (liporaxal, oral paclitaxel) compared to IV paclitaxel in patients with recurrent or metastatic breast cancer: OPERA (NCT03326102). 2019 San Antonio Breast Cancer Symposium, AACR. Cancer Res. 80(Suppl. 4), Abstract OT1-0-02 (2020).
- 73. . Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel. Int. J. Pharm. 511(2), 765–773 (2016).
- 74. Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin. Cancer Res. 5(11), 3379–3384 (1999).
- 75. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br. J. Cancer 84(1), 42–47 (2001).
- 76. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J. Clin. Oncol. 19, 1160–1166 (2001).
- 77. Coadministration of ritonavir strongly enhances the apparent oral bioavailability of docetaxel in patients with solid tumors. Clin. Cancer Res. 15(12), 4228–4233 (2009).
- 78. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res. 64(20), 7426–7431 (2004).
- 79. Ritonavir inhibitis intratumoral docetaxel metabolism and enhances docetaxel antitumor activity in an immunocompetent mouse breast cancer model. Int. J. Cancer 138(3), 758–769 (2016).
- 80. Phase I and pharmacokinetic study of oral paclitaxel. J. Clin. Oncol. 18(12), 2468–2475 (2000).
- 81. Phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A. Cancer Chemother. Pharmacol. 47(4), 347–354 (2001).
- 82. Phase II and pharmacologic study of weekly oral paclitaxel plus cyclosporine in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 20(23), 4508–4516 (2002).
- 83. Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer. Ann. Oncol. 14(2), 197–204 (2003).
- 84. Phase II and pharmacological study of oral paclitaxel (paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer. Br. J. Cancer 95(7), 794–800 (2006).
- 85. Novel paclitaxel formulations for oral application: a Phase I pharmacokinetic study in patients with solid tumours. Cancer Chemother. Pharmacol. 60(5), 635–642 (2007).
- 86. A novel self-microemulsifying formulation of paclitaxel for oral administration to patients with advanced cancer. Br. J. Cancer 95(6), 729–734 (2006).
- 87. . A pharmacokinetic and safety study of a novel polymeric paclitaxel formulation for oral application. Cancer Chemother. Pharmacol. 59(1), 43–50 (2007).
- 88. Oral bioavailability of a novel paclitaxel formulation (genetaxyl) administered with cyclosporin A in cancer patients. Anticancer Drugs 19(3), 275–281 (2008).
- 89. Boosting of orally administered paclitaxel by CYP3A4 inhibition. Dissertation VA de Weger, Utrecht University, ISBN: 978-94-6233-824-1, Utrecht, Chapter 2.5. 105–117 (2017).
- 90. A Phase I dose-escalation study of low dose metronomic treatment with oral paclitaxel, as ModraPac001 and ModraPac005, in combination with ritonavir. Clin. Pharmacol. Drug Dev.
doi:10.1002/cpdd.880 (2020) (Epub ahead of print). - 91. A Phase I study of oral paclitaxel with a novel P-glycoprotein inhibitor, HM30181A, in patients with advanced solid cancer. Cancer Res. Treat. 46(3), 234–242 (2014).
- 92. A Phase I study to evaluate safety, tolerability, pharmacokinetics and activity of oraxol in patients with advanced malignancies. J. Clin. Oncol. 36(15), 2526 (2018).
- 93. An international randomized cross-over bio-equivalence study of oral paclitaxel ± HM30181A (oraxol) compared with weekly intravenous (IV) paclitaxel 80 mg/m2 in advanced solid tumours. Ann. Oncol. 30(Suppl. 5), v159–v193 (2019).
- 94. Phase I/II study of weekly oraxol for the second-line treatment of patients with metastatic or recurrent gastric cancer. Oncologist 20(8), 896–897 (2015).
- 95. 800P. A Phase 1b study of oraxol in combination with ramucirumab in patients with gastric or oesophageal cancers who failed previous chemotherapy. Ann. Oncol. 30(Suppl. 5), v253–v324 (2019).
- 96. Oral paclitaxel in the treatment of metastatic breast cancer (MBC) patients. J. Clin. Oncol. 37(15), 1084 (2019).
- 97. Abstract GS06-01: oral paclitaxel with encequidar: the first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a Phase III clinical study in metastatic breast cancer. Cancer Res. 80(Suppl. 4), GS6–01 (2020). •• Demonstrated promising results for potential clinical implementation of oraxol in metastatic breast cancer.
- 98. A Phase II study of oraxol in the treatment of unresectable cutaneous angiosarcoma. J. Clin. Oncol. 38(15), 11517 (2020). •• Updated data presented at American Society of Clinical Oncology Virtual Scientific Program 2020.
- 99. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J. Clin. Oncol. 19, 1160–1166 (2001).
- 100. Phase II and pharmacological study of oral docetaxel plus cyclosporin A in anthracycline pre-treated metastatic breast cancer. Curr. Clin. Pharmacol. 9(2), 139–147 (2014).
- 101. Boosting of orally administered docetaxel by CYP3A4 inhibition [PhD thesis]. Utrecht University, Utrecht, The Netherlands, 39–51 (2017).
- 102. A Phase I dose escalation study of once-weekly oral administration of docetaxel as ModraDoc001 capsules or ModraDoc006 tablet in combination with ritonavir. Clin. Cancer Res. 25(18), 5466–5474 (2019).
- 103. A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir. Eur. J. Cancer 86, 217–225 (2017).
- 104. ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastasized castration-resistant prostate cancer (mCRPC): a multicenter Phase I study. ASCO 2020 Genitourinary Cancer Symposium. J. Clin. Oncol. 38(6), 79 (2020).
- 105. A multicenter Phase IIb trial to evaluate the efficacy and tolerability of ModraDoc006/r in subjects with metastatic castration-resistant prostate cancer (mCRPC), suitable for treatment with a taxane (NCT04028388). ASCO 2020 Genitourinary Cancer Symposium. J. Clin. Oncol. 38(6), 268 (2020). •• First clinical study with randomized comparison of oral and intravenous (IV) docetaxel in metastatic castration-resistant prostate cancer.
- 106. Addition of an oral docetaxel treatment (ModraDoc006/r) to androgen deprivation therapy (ADT) and intensity-modulated radiation therapy (IMRT) in patients with high risk N + M0 prostate cancer. ESMO 2019 Congress. Ann. Oncol. 30(Suppl. 5), v325–v355 (2019).
- 107. Modra Pharmaceuticals BV. A multicenter Phase IIa study to evaluate the efficacy and tolerability of ModraDoc006/r in patients with recurrent or metastatic HER2 negative breast cancer, suitable for treatment with a taxane. https://modrapharmaceuticals.com/clinical-trials/modradoc.html
- 108. Athenex. A dose regimen-finding study to evaluate the safety, tolerability, pharmacokinetics, and activity of Oradoxel monotherapy in subjects with advanced malignancies. https://clinicaltrials.gov/ct2/show/NCT02963168
- 109. Kinex Pharmaceuticals Inc. An open-label, pilot pharmacokinetic study to determine the bioavailability, safety, and tolerability of a single dose of Oradoxel in metastatic prostate cancer patients treated with intravenous docetaxel. www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370854
- 110. . Low-dose ritonavir for protease inhibitor pharmacokinetic enhancement. Ann. Pharmacother. 36(4), 702–706 (2002).
- 111. . Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy. Expert. Rev. Gastroenterol. Hepatol. 9(5), 547–558 (2015).
- 112. . Oral anticancer therapy: management of drug interactions. J. Oncol. Pract. 15(2), 81–90 (2019).
- 113. Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation. Br. J. Cancer 110(11), 2669–2676 (2014).
- 114. . Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Med. Res. Rev. 32(6), 1220–1262 (2012).
- 115. Oral efficacy and bioavailability of a novel taxane. Clin. Cancer Res. 6(5), 2070–2074 (2000).
- 116. A Phase I and pharmacokinetic study of BAY59: a novel taxane. Oncology 67(2), 123–129 (2004).
- 117. Multicenter, single arm, Phase II trial on the efficacy of ortataxel in recurrent glioblastoma. J. Neurooncol. 142(3), 455–462 (2019).
- 118. Phase II study of ortataxel in taxane-resistant breast cancer. J. Clin. Oncol. 26(15), 1066–1066 (2008).
- 119. The discovery of BMS-275183: an orally efficacious novel taxane. Bioorg. Med. Chem. 11(20), 4315–4323 (2003).
- 120. Phase I trial with BMS-275183, a novel oral taxane with promising antitumor activity. Clin. Cancer Res. 12(6), 1760–1767 (2006).
- 121. Effect of food on the pharmacokinetic behavior of the potent oral taxane BMS-275183. Clin. Cancer Res. 14(13), 4186–4191 (2008).
- 122. A Phase I safety and pharmacological study of a twice weekly dosing regimen of the oral taxane BMS-275183. Clin. Cancer Res. 13(13), 3906–3912 (2007).
- 123. A Phase I study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies. Invest. New Drugs 29(6), 1426–1431 (2011).
- 124. Bristol-Myers Squibb Company. Final clinical study report for study CA165020. A randomized, two-cohort Phase II study of two doses of BMS-275183 given on a weekly schedule in patients with pre-treated non-small cell lung cancer. www.clinicaltrialsregister.eu/ctr-search/trial/2004-000119-24/results
- 125. MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo. Mol. Cancer Ther. 2(9), 873–884 (2003).
- 126. Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumours. Cancer Chemother. Pharmacol. 60(2), 203–209 (2007).
- 127. A Phase II study of milataxel: a novel taxane analogue in previously treated patients with advanced colorectal cancer. Cancer Chemother. Pharmacol. 61(3), 453–458 (2008).
- 128. A Phase II study of intravenous (IV) milataxel (M) for the treatment of non-small cell lung cancer (NSCLC) refractory to platinum-based therapy. J. Clin. Oncol. 24(18), 7098–7098 (2006).
- 129. Phase I and pharmacokinetics (PK) of DJ-927, an oral taxane, in patients (Pts) with advanced cancers. J. Clin. Oncol. 22(14), 2028–2028 (2004).
- 130. Phase I development of a weekly dosing schedule for the oral taxane tesetaxel. J. Clin. Oncol. 30(15), 2555 (2012).
- 131. . Tesetaxel, a new oral taxane, in combination with capecitabine: a Phase I, dose-escalation study in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 68(6), 1565–1573 (2011).
- 132. Phase 2 trial of tesetaxel, an oral taxane, as 2nd-line therapy for patients with advanced gastro-oesophageal cancer. J. Clin. Oncol. 30(15), 4077 (2012).
- 133. Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer. J. Thorac. Oncol. 3(7), 745–750 (2008).
- 134. Activity of tesetaxel, an oral taxane, given as a single-agent in patients (Pts) with HER2-, hormone receptor ± (HR+) locally advanced or metastatic breast cancer (MBC) in a Phase 2 study. J. Clin. Oncol. 36(15), 1042 (2018).
- 135. CONTESSA: a multinational, multicenter, randomized, Phase III registration study of tesetaxel plus a reduced dose of capecitabine in patients (pts) with HER2-, hormone receptor ± (HR+) locally advanced or metastatic breast cancer (LA/MBC) who have previously received a taxane. J. Clin. Oncol. 37(15), 1107 (2019). •• Randomized clinical Phase III study investigating an all oral regime with tesetaxel/capecitabine in metastatic breast cancer.
- 136. CONTESSA TRIO: a multinational, multicenter, Phase (P) II study of tesetaxel (T) plus three different PD-(L)1 inhibitors in patients (Pts) with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly pts with HER2-metastatic breast cancer (MBC). J. Clin. Oncol. 38(15), 1111 (2020).
- 137. . Paclitaxel prodrugs: toward smarter delivery of anticancer agents. J. Med. Chem. 49(25), 7253–7269 (2006).
- 138. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann. Oncol. 22(4), 787–793 (2011).
- 139. Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer. Br. J. Cancer 98(10), 1608–1613 (2008).
- 140. Randomized Phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J. Thorac. Oncol. 3(7), 728–734 (2008).
- 141. Inhibition of pancreatic cancer cell viability and tumor growth through cell cycle arrest by an oral formulation of docetaxel. Int. J. Pharmacol. 15, 994–1000 (2019).
- 142. Enhanced oral absorption and anticancer efficacy of cabazitaxel by overcoming intestinal mucus and epithelium barriers using surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles. J. Control. Release 269, 423–438 (2018).
- 143. P-glycoprotein, CYP3A, and plasma carboxylesterase determine brain disposition and oral availability of the novel taxane cabazitaxel (Jevtana) in mice. Mol. Pharm. 12(10), 3714–3723 (2015).


