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First-in-Human Proof-of-Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to
Jasper Wouters1, Robert E Hunger2, Terence Garrod3
1Translational 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.
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.
Conclusion:
The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.
Insights
Intratumoral BQ788, an endothelin receptor B antagonist, was safe in melanoma patients. The treatment showed potential for reducing tumor viability and inhibiting lesion growth, supporting preclinical findings.
Area of Science:
- Oncology
- Dermatology
- Pharmacology
Background:
- Melanoma treatment remains a challenge, necessitating novel therapeutic strategies.
- Preclinical studies suggested intratumoral BQ788, an endothelin receptor B antagonist, could be effective.
- This study evaluated the safety and efficacy of BQ788 in human melanoma patients.
Purpose of the Study:
- To assess the safety and tolerability of intratumoral BQ788 in melanoma patients.
- To determine if preclinical findings regarding BQ788's effects could be replicated in humans.
- To explore BQ788's impact on tumor markers and lesion growth.
Main Methods:
- A proof-of-concept, first-in-human study involving five melanoma patients.
- Intralesional administration of BQ788 at escalating doses, with control lesions treated with phosphate-buffered saline (PBS).
- Tumor samples were analyzed for necrosis, cell proliferation (Ki67), receptor expression (EDNRB), and immune cell infiltration (CD3, CD31).
Main Results:
- BQ788 was well-tolerated with no observed adverse events across all doses.
- Decreased expression of EDNRB, Ki67, BCL2A1, and PARP3 was noted in BQ788-treated lesions.
- Increased vascularity (CD31) and lymphocyte infiltration (CD3) were observed, alongside an inverse correlation between EDNRB and HIF1A expression.
- One patient treated for over a week showed inhibited lesion growth.
Conclusions:
- Intralesional BQ788 demonstrated a favorable safety profile in melanoma patients.
- The treatment showed preliminary evidence of directly and indirectly reducing melanoma cell viability.
- Results support further investigation of BQ788 as a potential melanoma therapeutic agent.
