Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma

Madelon Q. Wentink, Henk M.W. Verheul, Sumanta K. Pal, Saby George, Johannes Voortman, Pongwut Danchaivijitr, Remi Adelaiye, Diane Poslinski, Adrienne Groman, Alan Hutson, Roberto Pili

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Patients received standard treatment with sunitinib (50 mg daily, 4 weeks on, 2 weeks off). During the second week of no sunitinib in the first cycle (week 6) patients received dalteparin monotherapy (in escalating doses). Combination therapy of the 2 agents was administered from the second cycle onward. Seventeen patients were enrolled at 3 dose levels of dalteparin. Results: Diarrhea and fatigue were the most frequent reported drug-related toxicities (41%). One dose-limiting toxicity (grade 3 anemia) was observed at the highest dose level of dalteparin. There were 4 partial responses (24%) and the median progression-free survival in this study was 14 months (95% confidence interval, 8.0-23.4). Anti-factor Xa levels were increased during combination therapy compared with dalteparin monotherapy. Conclusions: Combination therapy of sunitinib with therapeutic doses of dalteparin is safe and well tolerated. The increased anti-factor Xa levels during combination treatment suggest that sunitinib might increase the anticoagulation activity of dalteparin. The positive safety profile warrants prospective evaluation of the clinical benefit of this combination strategy in patients with ccRCC.

Original languageEnglish (US)
JournalClinical Genitourinary Cancer
DOIs
StateAccepted/In press - 2017

Fingerprint

Dalteparin
Renal Cell Carcinoma
Factor Xa
Therapeutics
Low Molecular Weight Heparin
sunitinib
Drug-Related Side Effects and Adverse Reactions
Disease-Free Survival
Fatigue
Anemia
Diarrhea
Confidence Intervals
Safety

Keywords

  • Dalteparin
  • LMWH
  • Renal cell carcinoma
  • Sunitinib
  • VEGF

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma. / Wentink, Madelon Q.; Verheul, Henk M.W.; Pal, Sumanta K.; George, Saby; Voortman, Johannes; Danchaivijitr, Pongwut; Adelaiye, Remi; Poslinski, Diane; Groman, Adrienne; Hutson, Alan; Pili, Roberto.

In: Clinical Genitourinary Cancer, 2017.

Research output: Contribution to journalArticle

Wentink, MQ, Verheul, HMW, Pal, SK, George, S, Voortman, J, Danchaivijitr, P, Adelaiye, R, Poslinski, D, Groman, A, Hutson, A & Pili, R 2017, 'Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma', Clinical Genitourinary Cancer. https://doi.org/10.1016/j.clgc.2017.07.004
Wentink, Madelon Q. ; Verheul, Henk M.W. ; Pal, Sumanta K. ; George, Saby ; Voortman, Johannes ; Danchaivijitr, Pongwut ; Adelaiye, Remi ; Poslinski, Diane ; Groman, Adrienne ; Hutson, Alan ; Pili, Roberto. / Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma. In: Clinical Genitourinary Cancer. 2017.
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abstract = "Background: Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Patients received standard treatment with sunitinib (50 mg daily, 4 weeks on, 2 weeks off). During the second week of no sunitinib in the first cycle (week 6) patients received dalteparin monotherapy (in escalating doses). Combination therapy of the 2 agents was administered from the second cycle onward. Seventeen patients were enrolled at 3 dose levels of dalteparin. Results: Diarrhea and fatigue were the most frequent reported drug-related toxicities (41{\%}). One dose-limiting toxicity (grade 3 anemia) was observed at the highest dose level of dalteparin. There were 4 partial responses (24{\%}) and the median progression-free survival in this study was 14 months (95{\%} confidence interval, 8.0-23.4). Anti-factor Xa levels were increased during combination therapy compared with dalteparin monotherapy. Conclusions: Combination therapy of sunitinib with therapeutic doses of dalteparin is safe and well tolerated. The increased anti-factor Xa levels during combination treatment suggest that sunitinib might increase the anticoagulation activity of dalteparin. The positive safety profile warrants prospective evaluation of the clinical benefit of this combination strategy in patients with ccRCC.",
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T1 - Phase I Study of Dalteparin in Combination With Sunitinib in Patients With Metastatic Clear Cell Renal Carcinoma

AU - Wentink, Madelon Q.

AU - Verheul, Henk M.W.

AU - Pal, Sumanta K.

AU - George, Saby

AU - Voortman, Johannes

AU - Danchaivijitr, Pongwut

AU - Adelaiye, Remi

AU - Poslinski, Diane

AU - Groman, Adrienne

AU - Hutson, Alan

AU - Pili, Roberto

PY - 2017

Y1 - 2017

N2 - Background: Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Patients received standard treatment with sunitinib (50 mg daily, 4 weeks on, 2 weeks off). During the second week of no sunitinib in the first cycle (week 6) patients received dalteparin monotherapy (in escalating doses). Combination therapy of the 2 agents was administered from the second cycle onward. Seventeen patients were enrolled at 3 dose levels of dalteparin. Results: Diarrhea and fatigue were the most frequent reported drug-related toxicities (41%). One dose-limiting toxicity (grade 3 anemia) was observed at the highest dose level of dalteparin. There were 4 partial responses (24%) and the median progression-free survival in this study was 14 months (95% confidence interval, 8.0-23.4). Anti-factor Xa levels were increased during combination therapy compared with dalteparin monotherapy. Conclusions: Combination therapy of sunitinib with therapeutic doses of dalteparin is safe and well tolerated. The increased anti-factor Xa levels during combination treatment suggest that sunitinib might increase the anticoagulation activity of dalteparin. The positive safety profile warrants prospective evaluation of the clinical benefit of this combination strategy in patients with ccRCC.

AB - Background: Based on the tumor-driven concomitant activation of angiogenesis and coagulation we conducted a phase I combination study of sunitinib with the low molecular weight heparin dalteparin in patients with metastatic clear cell renal cell carcinoma (ccRCC). Materials and Methods: Patients received standard treatment with sunitinib (50 mg daily, 4 weeks on, 2 weeks off). During the second week of no sunitinib in the first cycle (week 6) patients received dalteparin monotherapy (in escalating doses). Combination therapy of the 2 agents was administered from the second cycle onward. Seventeen patients were enrolled at 3 dose levels of dalteparin. Results: Diarrhea and fatigue were the most frequent reported drug-related toxicities (41%). One dose-limiting toxicity (grade 3 anemia) was observed at the highest dose level of dalteparin. There were 4 partial responses (24%) and the median progression-free survival in this study was 14 months (95% confidence interval, 8.0-23.4). Anti-factor Xa levels were increased during combination therapy compared with dalteparin monotherapy. Conclusions: Combination therapy of sunitinib with therapeutic doses of dalteparin is safe and well tolerated. The increased anti-factor Xa levels during combination treatment suggest that sunitinib might increase the anticoagulation activity of dalteparin. The positive safety profile warrants prospective evaluation of the clinical benefit of this combination strategy in patients with ccRCC.

KW - Dalteparin

KW - LMWH

KW - Renal cell carcinoma

KW - Sunitinib

KW - VEGF

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