Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial

Soledad Iseas, Enrique L Roca, Juan M O'Connor, Martin Eleta, Analia Sanchez-Luceros, Daniela Di Leo, Marcelo Tinelli, Maria L Fara, Eduardo Spitzer, Ignacio A Demarco, Giselle V Ripoll, Marina Pifano, Juan Garona, Daniel F Alonso, Soledad Iseas, Enrique L Roca, Juan M O'Connor, Martin Eleta, Analia Sanchez-Luceros, Daniela Di Leo, Marcelo Tinelli, Maria L Fara, Eduardo Spitzer, Ignacio A Demarco, Giselle V Ripoll, Marina Pifano, Juan Garona, Daniel F Alonso

Abstract

Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Clinical trial registration www.clinicaltrials.gov NCT01623206.

Keywords: Drug repurposing; Gastrointestinal cancer; Hemostasis; Tumor perfusion; Vasopressin peptide analog; von Willebrand factor.

Conflict of interest statement

D. Di Leo, M. Tinelli, M.L. Fara and E. Spitzer are employees of Elea-Phoenix Laboratories. I.A. Demarco is employee of Chemo-Romikin. G.V. Ripoll, M. Pifano, J. Garona and D.F. Alonso have served in a consultant/advisory role for Elea-Phoenix Laboratories and Chemo-Romikin. G.V. Ripoll and D.F. Alonso are inventors in a patent related to the therapeutic use of vasopressin analogs, which belongs to their academic institution. All other authors have no conflicts of interests to declare.

Figures

Fig. 1
Fig. 1
Bleeding score after dDAVP administration. Rectal bleeding was graded from 0 to 10 points using a score based on the Chutkan scale, as described in Methods section. Results obtained in patients from the expansion cohort (n = 12), receiving the selected daily dose of 0.5 µg/kg for two consecutive days, are shown. Patients were evaluated before the first infusion of dDAVP (day 0), one (day 1) and four (day 4) days later, and on the last follow-up (day 14). Data represent median ± interquartile range. **P 

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