1200TiP - Phase Ia/Ib study of RS-0139, a novel tumor-targeted delivery of docetaxel, in patients with recurrent, locally advanced, or metastatic non-small cell lung cancer (NSCLC)

Background

Docetaxel (DTX) is an anti-microtubule agent registered for multiple indications and is usually administered 3-weekly at doses of 60-100 mg/m². Important limitations of DTX include acute hypersensitivity reactions, neutropenia, neuropathy, fatigue and nausea. RS-0139 is developed as a DTX-releasing, tumor-targeted prodrug. DTX is covalently bound to a polymer backbone, together with a targeting peptide, which shows high affinity to a_vb₃, a_vb₅ and a_vb₆ integrin receptors highly expressed on tumor cell surface. Once RS-0139 is up-taken by the cell, the covalent bond is cleaved to release DTX in the cytoplasm. RS-0139 gains the investigational new drug status since DTX is covalently modified for the targeted treatment. The physical properties of RS-0139, pharmacokinetic profile and improved aqueous solubility may provide an advantage over the currently used taxanes. In preclinical studies, enzymatically cleavable covalent conjugation of DTX enabled sustained-release inside the tumor, reducing adverse effects due to limited circulating free DTX. Hence, RS-0139 showed superior tolerability than DTX in healthy animals. Besides, the dosing frequency decreased owing to the increased half-life. Preclinical data strongly support the clinical translation of this novel nanomedicine for the treatment of solid tumors.

Trial design

This is a phase Ia/Ib open-label, multicenter, dose-escalation and expansion study to evaluate the safety and tolerability of RS-0139 monotherapy in NSCLC. Patients who progressed after standard therapy are eligible for the study. In Phase Ia, patients receive RS-0139 (IV) at escalating doses (75-200 mg/m²). The protocol consists of an accelerated titration design until the recommended dose for Phase Ib is elicited and switched to standard 3+3 design in case of grade 2 toxicity. Phase Ib will be initiated following the determination of the recommended dose for RS-0139 upon evaluation of all available safety and PK data and 6 patients will receive 3 cycles in every 21 days. The primary endpoint is the determination of the MTD of RS-0139. The study is open for enrollment in 2 sites. Two of the planned 16 patients have been enrolled to date.

Clinical trial identification

NCT04261413.

Editorial acknowledgement

Legal entity responsible for the study

RS Research.

Funding

RS Research.

Disclosure

G. Nomak: Financial Interests, Personal, Full or part-time Employment: RS Research; Financial Interests, Personal, Member of the Board of Directors: RS Research; Financial Interests, Personal, Stocks/Shares: RS Research. Y. Eralp: Financial Interests, Personal, Advisory Role: Roche, Novartis, MSD Oncology; Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Other: Gilead, Roche Molecular Diagnostics. F.P. Yumuk: Financial Interests, Personal, Advisory Role: BMS, Takeda, Novo Nordisk; Financial Interests, Personal, Sponsor/Funding: EMD Serono, MSD, Pfizer; Financial Interests, Personal, Advisory Board: Roche. H.S. Nomak: Financial Interests, Personal, Ownership Interest: RS Research; Financial Interests, Personal, Member of the Board of Directors: RS Research; Financial Interests, Personal, Stocks/Shares: RS Research. R. Sanyal: Financial Interests, Personal, Ownership Interest: RS Research; Financial Interests, Personal, Member of the Board of Directors: RS Research; Financial Interests, Personal, Stocks/Shares: RS Research; Financial Interests, Personal, Royalties: Bogazici University. All other authors have declared no conflicts of interest.