Skip to main content

A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors

Summary

Purpose The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. Experimental design TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. Results Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m2 over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m2 developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m2, was declared as MTD. Treatment-related grade 3–4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3–4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R and 996 (1333) L/m2 for S,S, and 2174 (2526) L/h-m2 for S,R and 2670 (2988) L/h-m2 for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. Conclusions TLC388 at 50 mg/m2 on the current treatment schedule is generally safe and well tolerated.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Pommier Y (2006) Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6:789–802

    CAS  Article  PubMed  Google Scholar 

  2. Long HJ, Bundy BN, Grendys EC et al (2005) Randomized phase III trials of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23:4626–4633

    CAS  Article  PubMed  Google Scholar 

  3. Cunningham D, Pyrhonen S, James RD et al (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418

    CAS  Article  PubMed  Google Scholar 

  4. Huang G, Wang H, Yang LX (2010) Enhancement of radiation-induced DNA damage and inhibition of its repair by a novel camptothecin analog. Anticancer Res 30:937–944

    PubMed  Google Scholar 

  5. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    CAS  Article  PubMed  Google Scholar 

  6. Rowinsky EK, Grochow LB, Ettinger DS et al (1994) Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. Cancer Res 54:427–436

    CAS  PubMed  Google Scholar 

  7. Rowinsky EK, Grochow LB, Hendricks CB et al (1992) Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 10:647–656

    CAS  PubMed  Google Scholar 

  8. Verweij J, Lund B, Beijnen J et al (1993) Phase I and pharmacokinetics study of topotecan, a new topoisomerase I inhibitor. Ann Oncol 4:673–678

    CAS  PubMed  Google Scholar 

  9. Attard G, de Bono JS (2011) Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients. Clin Cancer Res 17:3867–3875

    CAS  Article  PubMed  Google Scholar 

Download references

Conflict of interest

Yunlong Tseng, Min-Wen Kuo, Wendy B. Mach, and Shu-Chi Hsu are the employees of the study sponsor (Taiwan Liposome Company, Inc.). The remaining authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sanjay Goel.

Additional information

Sharad Ghamande and Chia-Chi Lin contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ghamande, S., Lin, CC., Cho, D.C. et al. A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors. Invest New Drugs 32, 445–451 (2014). https://doi.org/10.1007/s10637-013-0044-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-013-0044-7

Keywords

  • Camptothecin
  • Topotecan
  • Phase 1 trial
  • Hypoxia-inducible factor
  • Topoisomerase