1100P - Open-label non-randomized phase IB study to characterize the safety, tolerability and recommended dose of tinostamustin in combination with nivolumab in patients with advanced melanoma (ENIGMA)

Background

Melanoma patients (pts) progressing after immune checkpoint inhibitors (ICI) and BRAF targeting therapy have a poor prognosis. We explored the feasibility of a combination of the alkylating deacetylase inhibition fusion molecule tinostamustine in sub-chemotherapeutic concentrations and nivolumab.

Methods

This study was initiated to characterize dose-limiting toxicity (DLT) and the recommended phase-2 dose (RP2D) of tinostamustine and nivolumab in pts with advanced melanoma. Tinostamustine was administered at escalating doses of 15 and 30 mg/m² in a 3-plus-3 design, nivolumab was added at a dose of 3 mg/kg on day 15, both given i.v. every 2 weeks until toxicity or tumor progression (with the option of treatment-beyond progression).

Results

17 pts were included into the study including 4 pts treated with tinostamustine 15 mg/m² over 60 min and 13 pts treated with tinostamustine 30 mg/m² over 60 min. 13/17 pts (77%) received prior ICI, 7/17 pts (41%) had unfavorable melanoma types (acral, mucosal, uveal) and 10/17 pts (59%) elevated baseline lactate dehydrogenase (LDH). No DLT was documented and the RP2D for tinostamustine in combination with nivolumab was defined as 30mg/m²over 60 min. We observed one nivolumab-associated serious adverse event (SAE) of immune-related pneumonitis. Mean treatment duration was 22 weeks; 3 patients received ≤4 weeks of study treatment due to early progression. Disease stabilization among 15 evaluable pts was 47%, including 3pts (20%) with a confirmed partial response. Median progression-free survival was 8.3 weeks (95% CI 2.4 to 15.4 weeks), median overall survival 19.1 weeks (95% CI 2.4 to 41 weeks). No severe myelosuppression was observed except a single case of grade 3 leucocytopenia.Ex vivo T-cell stimulation and ELISA from blood samples revealed induction of adaptive T-cell and antibody responses against tumor-associated antigens.

Conclusions

Tinostamustine at an immune-modulatory dose of 30 mg/m² over 60 min is safe when co-administered with nivolumab 3mg/kg and resulted in 47% disease stabilization and 20% objective radiological responses in pts with advanced melanoma failing standard ICI treatment.

Clinical trial identification

NCT03903458.

Editorial acknowledgement

Legal entity responsible for the study

Clinical Trial Unit, Cantonal Hospital, 9007 St. Gallen, Switzerland.

Funding

Mundipharma.

Disclosure

M. Joerger: Financial Interests, Institutional, Coordinating PI, Clinical study activity: Basilea, Bayer, BMS, Immunophotonics, MSD, Novartis, Roche; Financial Interests, Institutional, Other, Clinical study activity: Daiichi Sankyo; Financial Interests, Institutional, Local PI, Clinical study activity: InnoMedica; Non-Financial Interests, Advisory Role: Novartis, AstraZeneca, Basilea, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi. K. Koster: Other, Personal, Other, Travel grant: Jansen; Other, Personal, Officer, Travel grant: Takeda. D. Hess: Financial Interests, Personal, Stocks/Shares: Novartis, Roche. Y. Metaxas: Financial Interests, Personal, Other, Travel grant: Roche. S. Aeppli: Financial Interests, Institutional, Advisory Board: BMS, Pfizer, Merck. T.P. El Saadany: Non-Financial Interests, Personal, Writing Engagement: Merck, Pfizer. R.A.F. von Moos: Non-Financial Interests, Personal, Advisory Board: Gilead, Merck, Eli Lilly, Pierre Fabre, MSD, Vifor, GSK, PharmaMar, Sanofi; Financial Interests, Institutional, Research Funding: Bayer; Financial Interests, Personal, Other, Travel grant: Takeda, Pierre Fabre. All other authors have declared no conflicts of interest.