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Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules

  • PHASE I STUDIES
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Summary

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0–2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m2/day. At 3.0 mg/m2/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m2/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m2/day. The maximum tolerated dose was 3 mg/m2/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m2/day and 3.0 mg/m2/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

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Acknowledgments

We thank all patients who participated in these studies. We thank Kazuhito Arakawa, Takashi Arima, Hideki Kawamata, Kazuaki Matsuoka, Hideki Nagase and Toshiyuki Toko for assistant in the clinical preparation and the data analysis.

Funding

The research was supported by Delta-Fly Pharma Inc.

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Authors and Affiliations

  1. Cedars-Sinai Medical Center, Beverly Hills, CA, USA

    Kamalesh Sankhala

  2. Institute for Drug Development, Cancer Therapy & Research Center, San Antonio, TX, USA

    Chris H. Takimoto & K. Burns

  3. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Alain C. Mita

  4. The Center for Cancer and Blood Disorders/SCRI, Fort Worth, TX, USA

    Henry Xiong

  5. Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jordi Rodón

  6. Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Amir Mehrvarz Sarshekeh & Scott Kopetz

  7. Delta-Fly Pharma Inc., Tokushima, Japan

    Kenzo Iizuka

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  1. Kamalesh Sankhala
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Correspondence to Scott Kopetz.

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All authors declare no potential conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Written informed consent to participate in the study was obtained from each patient before study enrollment and the performance of any study-specific procedures.

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Sankhala, K., Takimoto, C.H., Mita, A.C. et al. Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules. Invest New Drugs 37, 76–86 (2019). https://doi.org/10.1007/s10637-018-0602-0

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