Targeting the endothelin axis with atrasentan, in combination with IFN-alpha, in metastatic renal cell carcinoma.
BACKGROUND
The endothelin system is involved in tumour growth. Atrasentan, a selective endothelin-A-receptor antagonist, blocks endothelin signalling. This phase I trial studied combining treatment of interferon-alpha (IFN-α) with atrasentan in renal cell carcinoma (RCC).


METHODS
This study evaluated the safety and tolerance of IFN-α (9MU subcutaneously (s.c.) three times a week) in combination with atrasentan (2.5, 5 and 10 mg orally once daily) in untreated metastatic RCC. Cohort 10 mg was extended to obtain insights in efficacy and pharmacodynamics.


RESULTS
Observed toxicities mainly consisted of known IFN-like toxicities (anorexia, chills, fever, fatigue and nausea), and of nasal congestion (associated to atrasentan). None of these toxicities were considered dose limiting. Cohort 10 mg was extended up to 32 patients; in a subset of patients treated according to the protocol (n=27), median overall survival (OS) was 17.3 months. One patient (3.1%) showed a partial response lasting 14.3 months. In an exploratory analysis, we observed that in the subset of patients with declining vascular endothelial growth factor (VEGF) levels (in combination with rising Endothelin-1 levels), median OS was 22.2 months compared with 2.2 months in patients with increasing VEGF levels.


CONCLUSIONS
Combination treatment of IFN-α 9MU-α s.c. three times a week and atrasentan 10 mg once daily is tolerated. Clinical activity, especially OS, and biomarkers in our view warrant further studies targeting the endothelin axis.
Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands. g.groenewegen@umcutrecht.nl
G
G
Groenewegen
M
M
Walraven
J
J
Vermaat
B
B
de Gast
E
E
Witteveen
R
R
Giles
J
J
Haanen
E
E
Voest
D000328:Adult; D000368:Aged; D000077868:Atrasentan; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D016232:Endothelins; D016898:Interferon-alpha; D011759:Pyrrolidines; D000077868:Atrasentan