IL believe: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab or standard-of-care chemotherapy in patients with locally advanced or metastatic solid tumors.

Abstract

TPS2695 Background: Advances in immunotherapy have led to significantly improved survival and quality of life in some cancer patients, but many with less immunogenic tumor types derive suboptimal clinical benefit. Recombinant human interleukin-2 (IL-2, aldesleukin) can induce a response rate of ̃15% in metastatic renal cell carcinoma and metastatic melanoma, yet toxicities (vascular leak syndrome, cytokine storm) have limited its use. TransCon IL-2 β/γ, a novel prodrug with sustained release of a receptor-selective IL-2 (IL-2 β/γ), was designed to optimally address drawbacks of aldesleukin: potent activation of undesired IL-2Rα+ cell types and high Cmax with rapid clearance. TransCon IL-2 β/γ comprises 3 main components: IL-2 β/γ, a methoxy polyethylene glycol (mPEG) carrier molecule, and a linker connecting the two. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the mPEG carrier through cleavage of the TransCon Linker. This results in a lower Cmax and much longer effective t½ of free IL-2 β/γ compared to aldesleukin. PD-1 expression at the cell surface of activated cytotoxic T cells and natural killer cells provides a clear rationale to study TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: IL Believe is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced or metastatic solid tumors. All patients need ≥1 measurable lesion per RECIST 1.1 and an ECOG score of ≤ 2. The primary objectives are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of intravenous (IV) TransCon IL-2 b/g alone (Part 1) or with 200 mg IV pembrolizumab in solid tumors where pembrolizumab monotherapy may have clinical activity (Part 2). Each part will enroll ̃15 patients. Part 3, Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon IL-2 β/γ at the RP2D determined in Part 2, combined with chemotherapy. Platinum Resistant Ovarian Cancer is currently planned for dose expansion with other indication specific cohorts to be included in a subsequent amendment. Each cohort will be analyzed using a Simon 2-stage design and will enroll ̃56 patients. Other key objectives include the evaluation of pharmacokinetics, pharmacodynamic biomarkers, and antitumor activity according to RECIST 1.1. Recruitment started in January 2022 and is ongoing (NCT05081609). Clinical trial information: NCT05081609.