Phase 1a dose-escalation study of RS-0139: A novel tumor-targeted nanomedicine for advanced solid tumors.

e15006 Background: RS-0139 is a tumor-targeted prodrug designed to enhance the therapeutic index of docetaxel (DTX) by selectively delivering the active agent to tumor tissues. DTX is covalently bound to a polymer backbone, together with a targeting peptide, which shows a high affinity to α v β 3 , α v β 5 and α v β 6 integrin receptors highly overexpressed on the tumor cell surface. Once RS-0139 is up-taken by the cell, the covalent bond is cleaved to release DTX. RS-0139 gains the investigational new drug status since DTX is covalently modified for the targeted treatment. Physical properties of RS-0139, pharmacokinetic (PK) profile and improved aqueous solubility may provide an advantage over taxanes. In preclinical studies, the enzymatically cleavable covalent conjugation of DTX enabled sustained release inside the tumor, reduced off-target toxicity, and enhanced antitumor efficacy compared to DTX. This first-in-human, multicenter, open-label, dose-escalation study aimed to assess the safety, tolerability and PK of RS-0139 in patients with advanced solid tumors. Methods: Eligiblepatients (18-75 years) with recurrent, locally advanced, or metastatic solid tumors and ECOG PS 0-1 were enrolled and received a single dose of RS-0139 intravenously using an accelerated titration design. The primary objectives were assessing safety and tolerability and determining the maximum tolerated dose (MTD) of RS-0139 monotherapy. Dose levels (DL) included 60, 75, and 100 mg/m². Safety assessments included dose-limiting toxicities (DLTs) and adverse events (AEs). PK analyses were conducted, and dose escalation decisions were made under the guidance of an independent data monitoring committee (IDMC). Results: Eight patients (median age: 61 years) were enrolled across three dose levels (DL 1: 75 mg/m², n = 3; DL 2: 100 mg/m², n = 2; DL -1: 60 mg/m², n = 3). 50% of patients received ≥3 lines of systemic therapy previously.The tumor types included NSCLC, ovarian and endometrial cancers.At DL 1, one patient experienced grade 4 neutropenia, successfully managed with G-CSF; no other treatment-related DLTs occurred. PK analysis at this dose level revealed a 4.4-fold longer half-life and > 300-fold higher AUC for RS-0139 than DTX. At DL 2, febrile neutropenia and thrombocytopenia were observed in two patients, prompting dose de-escalation. At DL -1, no grade ≥3 toxicities were reported, and the treatment was well tolerated. The TRAEs observed at DL -1 included vomiting, nausea, diarrhea, fatigue, myalgia and arthralgia, all of which were grade 1. Conclusions: RS-0139 exhibited a manageable safety profile at 60 mg/m², with no DLTs reported. The IDMC identified DL 1 as the MTD and recommended DL -1 as the optimal dose for Ph1b. The prolonged half-life and elevated AUC indicate the potential for improved efficacy at lower doses. The study has now advanced to Ph1b to further assess the efficacy and safety of RS-0139 in a larger patient cohort. Clinical trial information: NCT04261413 .