A phase I, open-label study of pasireotide in patients with BRAF- and NRAS-wild type, unresectable and or metastatic melanoma

Background

Somatostatin receptors (SSTR) and insulin-like growth factor receptors (IGFR) have been shown to be strongly expressed in melanoma cells. This phase I study evaluated the preliminary safety, pharmacokinetics (PK), and efficacy of pasireotide, a somatostatin analogue with broad SSTR affinity, in patients (pts) with BRAF- and NRAS-wild type, confirmed unresectable and/or metastatic melanoma.

Methods

Patients (planned N = 18) with unresectable (stage III) and/or metastatic (stage IV) melanoma and confirmed unresectable and/or metastatic Merkel cell carcinoma (MCC) were eligible. The study was divided into 3 phases: screening, intra-patient dose-escalation (8 weeks), and follow-up (6 months). The primary endpoint was safety during the 8-wk escalation phase. Secondary endpoints included safety at study completion, disease control rate (DCR, by CT or MRI per RECIST 1.0), PK, effect of pasireotide on biomarkers.

Results

The study was terminated early due to slow recruitment after 2 years (y) from study initiation. Of the 10 melanoma pts enrolled, 50% completed the dose-escalation phase and entered follow-up. Median age: 71.5 y (range, 60-77); ≥ 65 y: 7 (70%) pts; 8 (80%) males. Median duration of exposure: 6.71 wks (range, 1.6-8.1) for escalation phase; 7.57 wks (range, 1.6-32.1) for overall phase. Most frequent adverse events (AEs) during escalation phase in ≥ 2 (20%) pts were: diarrhea (50%), nausea (50%), fatigue (20%), hyperglycemia (20%), hypophosphatemia (20%), chills (20%), and tumor pain (20%). Grade 3-4 drug-related AEs were reported in 1 pt. One pt had partial response (PR) and one had stable disease (SD). DCR was 20% and objective response rate was 10%. PK exposures increased with increasing dose. Low levels of tumor biomarkers were consistently observed in pts with response (PR or SD).

Conclusions

In pts with BRAF- and NRAS-wild type melanoma, pasireotide is well tolerated and its safety profile is consistent with prior reports in other indications with the exception of lower frequency of hyperglycemia. Preliminary anti-tumor efficacy of pasireotide is encouraging. Pasireotide may be a candidate for combination therapy in advanced melanoma.

Clinical trial identification

NCT01652547

Legal entity responsible for the study

Novartis Pharmaceutical Corporation

Funding

Novartis Pharmaceutical Corporation

Disclosure

R. Dummer: Research funding from Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline (GSK), and has a consultant or advisory board relationship with Novartis, MSD, BMS, Roche, GSK, and Amgen outside the submitted work. O.A. Michielin: Has a consultant or advisory board relationship with Bristol-Myers Squibb, Novartis, Roche, Merck Sharp & Dhome. S.M. Goldinger: Has a consultant or advisory board relationship with Bristol-Myers Squibb, Merck Sharpe & Dhome, Roche, and Novartis. F. Campigotto: Has employment and stock ownership with Novartis and has receives research funding from Novartis. U. Kriemler-Krahn: Has employment and stock ownership with Novartis. H. Schmid: Has employment and stock ownership with Novartis, received research funding from Novartis. A. Pedroncelli: Has employment with Novartis. D. Schadendorf: Institution receives research funding from Bristol-Myers Squibb (BMS) and Merck Sharp & Dhome, and he has a consultant or advisory board relationship with Amgen, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dhome, Pfizer, Novartis and Roche. All other authors have declared no conflicts of interest.