Skip to main content

Advertisement

SpringerLink
Log in

A phase I study of DHP107, a mucoadhesive lipid form of oral paclitaxel, in patients with advanced solid tumors: Crossover comparisons with intravenous paclitaxel

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Purpose This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. Patients and methods Patients with advanced solid tumors refractory to all standard treatments were administered a single oral dose of DHP107 on a dose-escalating schedule (60–600 mg/m2) during the first chemotherapy cycle, and intravenous paclitaxel 175 mg/m2 during subsequent cycles. Cohorts of 3 patients were treated at each dose level provided no DLTs were observed. The pharmacokinetics of paclitaxel and its metabolites were investigated for oral DHP107 and intravenous paclitaxel. Results Thirty-four patients were enrolled. Dose-limiting toxicities were not observed, even at the highest dose level (600 mg/m2). Further dose escalation was not performed because pharmacokinetics did not increase proportionally at doses above 250 mg/m2. The coefficient of variance of AUClast DHP107 ranged from 11.8 % to 34.0 %, comparable to 24.4 % of intravenous paclitaxel 175 mg/m2. There were no grade 4 toxicities, whereas grade 3 toxicities included diarrhea (12.1 %), neutropenia (6.1 %) and fatigue (3.0 %). While no objective responses were observed, 11 patients (33.3 %) showed stable disease. Conclusions DHP107 was safe and feasible in patients with advanced malignancies. As exposure of paclitaxel plateau among patients receiving more than 250 mg/m2 of DHP107, the dose escalation of DHP107 may be limited to 250 mg/m2 in further clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Vergote I, Trope CG, Amant F et al (2010) Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943–53

    Article  PubMed  CAS  Google Scholar 

  2. Kang HJ, Chang HM, Kim TW et al (2008) A phase II study of paclitaxel and capecitabine as a first-line combination chemotherapy for advanced gastric cancer. Br J Cancer 98:316–22

    Article  PubMed  CAS  Google Scholar 

  3. Di Leo A, Gomez HL, Aziz Z et al (2008) Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544–52

    Article  PubMed  Google Scholar 

  4. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–50

    Article  PubMed  CAS  Google Scholar 

  5. Weiss RB, Donehower RC, Wiernik PH et al (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8:1263–8

    PubMed  CAS  Google Scholar 

  6. Liebmann J, Cook JA, Mitchell JB (1993) Cremophor EL, solvent for paclitaxel, and toxicity. Lancet 342:1428

    Article  PubMed  CAS  Google Scholar 

  7. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–36

    Article  PubMed  CAS  Google Scholar 

  8. Zhang M, Tao W, Pan S et al (2009) Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts. Anticancer Drugs 20:355–63

    Article  PubMed  Google Scholar 

  9. Seidman AD, Berry D, Cirrincione C et al (2008) 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 26:1642–9

    Article  PubMed  CAS  Google Scholar 

  10. Malingre MM, Beijnen JH, Rosing H et al (2001) Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br J Cancer 84:42–7

    Article  PubMed  Google Scholar 

  11. Malingre MM, Beijnen JH, Rosing H et al (2001) A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A. Canc Chemother Pharmacol 47:347–54

    Article  CAS  Google Scholar 

  12. Hong JW, Lee IH, Kwak YH et al (2007) Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation. Mol Cancer Ther 6:3239–47

    Article  PubMed  CAS  Google Scholar 

  13. Shin BS, Kim HJ, Hong SH et al (2009) Enhanced absorption and tissue distribution of paclitaxel following oral administration of DHP 107, a novel mucoadhesive lipid dosage form. Canc Chemother Pharmacol 64:87–94

    Article  CAS  Google Scholar 

  14. Britten CD, Baker SD, Denis LJ et al (2000) Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel. Clin Cancer Res 6:3459–68

    PubMed  CAS  Google Scholar 

  15. Veltkamp SA, Alderden-Los C, Sharma A et al (2007) A pharmacokinetic and safety study of a novel polymeric paclitaxel formulation for oral application. Canc Chemother Pharmacol 59:43–50

    Article  CAS  Google Scholar 

  16. Veltkamp SA, Rosing H, Huitema AD et al (2007) Novel paclitaxel formulations for oral application: a phase I pharmacokinetic study in patients with solid tumours. Cancer Chemother Pharmacol 60:635–42

    Article  PubMed  CAS  Google Scholar 

  17. Malingre MM, Terwogt JM, Beijnen JH et al (2000) Phase I and pharmacokinetic study of oral paclitaxel. J Clin Oncol 18:2468–75

    PubMed  CAS  Google Scholar 

  18. Bardelmeijer HA, Ouwehand M, Malingre MM et al (2002) Entrapment by Cremophor EL decreases the absorption of paclitaxel from the gut. Canc Chemother Pharmacol 49:119–25

    Article  CAS  Google Scholar 

  19. Kantarjian H, Giles F, Wunderle L et al (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–51

    Article  PubMed  Google Scholar 

  20. Rahman A, Korzekwa KR, Grogan J et al (1994) Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2 C8. Cancer Res 54:5543–6

    PubMed  CAS  Google Scholar 

  21. Sparreboom A, Huizing MT, Boesen JJ et al (1995) Isolation, purification, and biological activity of mono- and dihydroxylated paclitaxel metabolites from human feces. Canc Chemother Pharmacol 36:299–304

    Article  CAS  Google Scholar 

  22. Chu Z, Chen JS, Liau CT et al (2008) Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients. Anticancer Drugs 19:275–81

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by a grant from DAE HWA Pharmaceutical Co. and Gangwon Leading Industry Office by Korean government

Conflict of Interest

Hyeyoun Kim works for DAE HWA Pharmaceutical Co., Ltd. as a commissioner, and has a leadership position to disclose.

Author information

Authors and Affiliations

  1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Poongnap-dong, Songpa-gu, Seoul, 138-736, South Korea

    Yong Sang Hong, Kyu-pyo Kim, Min-Hee Ryu, Jae-Lyun Lee, Heung Moon Chang, Yoon-Koo Kang & Tae Won Kim

  2. Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Hyeong-Seok Lim & Kyun-Seop Bae

  3. Product Planning & Development Department, DAE HWA Pharmaceutical Co., Ltd., Hoengseong, Gangwon, South Korea

    Hyeyoun Kim

Authors
  1. Yong Sang Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyu-pyo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyeong-Seok Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyun-Seop Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min-Hee Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jae-Lyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heung Moon Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoon-Koo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hyeyoun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tae Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae Won Kim.

Additional information

Yong Sang Hong and Kyu-pyo Kim are equally contributed to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, Y.S., Kim, Kp., Lim, HS. et al. A phase I study of DHP107, a mucoadhesive lipid form of oral paclitaxel, in patients with advanced solid tumors: Crossover comparisons with intravenous paclitaxel. Invest New Drugs 31, 616–622 (2013). https://doi.org/10.1007/s10637-012-9841-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-012-9841-7

Keywords

Search

Navigation