First-in-Human Proof-of-Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to Melanoma Skin Metastases.
BACKGROUND
This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.


METHODS
Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.


RESULTS
No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.


CONCLUSIONS
The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.
Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium; ronit.lahav@melcure.com jasper.wouters@med.kuleuven.be.
Jasper
J
Wouters
Department of Dermatology, Inselspital, Bern, Switzerland;
Robert E
RE
Hunger
Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium;
Terence
T
Garrod
MelCure SA, Eclosion SA, Plan les Ouates, Switzerland.
Benoit
B
Dubuis
Department of Dermatology, Inselspital, Bern, Switzerland;
Thomas
T
Hunziker
Translational Cell and Tissue Research, Department of Imaging and Pathology, University of Leuven (KU Leuven), Leuven, Belgium;
Joost J
JJ
van den Oord
MelCure SA, Eclosion SA, Plan les Ouates, Switzerland.
Ronit
R
Lahav-le Coutre
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018797:Cell Cycle Proteins / Q000235:genetics; D004334:Drug Administration Schedule; D065131:Endothelin B Receptor Antagonists / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D015552:Injections, Intralesional; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000556:secondary; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D018797:Cell Cycle Proteins; C000588596:EDNRB protein, human; D065131:Endothelin B Receptor Antagonists; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D044023:Receptor, Endothelin B; C086539:BQ 788; C480979:PARP3 protein, human; D011065:Poly(ADP-ribose) Polymerases