Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel

Abstract

Background

A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82.

Methods

Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1–14, a treatment break on days 15–20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3′-deoxy-3′-18F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models.

Results

14 patients were enrolled and treated with median 3.5 cycles (range 0–12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUVmax decreased by − 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUVmax decreased − 44% (p = 0.03).

Conclusions

The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.

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Acknowledgements

The authors would like to thank the nurses and research specialists of the UWCCC Phase I Program for their efforts in managing this trial. The authors would also like to thank the WIMR PET imaging staff especially Chris Jaskowiak for her help with PET/CT scanning, the UW Cyclotron for preparing the radiotracer, and the patients for their participation in the study.

Funding

This study was funded by Tyrogenex. Support was also provided by the National Cancer Institute (NCI) awards P30 CA014520 and UM1 CA186716. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Correspondence to Justine Yang Bruce.

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Author Chris Liang is a shareholder of Tyrogenex.

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Informed consent was obtained from all individual participants included in the study.

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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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Cite this article

Scarpelli, M., Rampurwala, M., Eickhoff, J. et al. Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel. Cancer Chemother Pharmacol 82, 211–219 (2018). https://doi.org/10.1007/s00280-018-3599-3

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Keywords

  • FLT PET/CT
  • VEGFR-TKI
  • Combination therapy
  • Docetaxel
  • Anti-angiogenic therapy
  • VEGF