Abstract
Background:
SAR444245 (THOR-707) is a well differentiated and improved recombinant human interleukin-2 (IL-2) molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the IL2 receptor (IL2R) beta/gamma subunits. In animal models, SAR444245 showed anti-tumor benefits, and with no severe side effects, both as a single agent as well as when combined with anti-PD1 compared with historical data from aldesleukin. Sanofi has found that non-Hodgkin lymphoma (NHL) cell lines do not express IL2R-beta/gamma. Furthermore, level of IL2R-beta/gamma single cell mRNA levels from peripheral T cells or tumor infiltrating T cells are similar between samples from patients with NHL and lung cancer. Therefore, although the first-in-human (HAMMER) study is conducted in patients with solid tumor, the recommended Phase 2 dose selected is hypothesized to be applicable to patients with either lymphoma or solid tumor. In addition to demonstrating CD8+ T cells and NK cells expansion in HAMMER study, SAR444245 also improves human CD19-directed CAR-T cell expansion in vitro. HAMMER study has shown promising preliminary efficacy and manageable safety profile for SAR444245 with or without pembrolizumab in multiple solid tumors. This Phase 2 study is designed to evaluate the clinical benefit of 1) SAR444245 with pembrolizumab for checkpoint inhibitor-naïve patients with relapsed or refractory classic Hodgkin lymphoma (cHL), and 2) SAR444245 monotherapy for patients with diffuse large B-cell lymphoma (DLBCL) who have stable or progressive disease after having received Health Authority approved CD19-directed CAR-T cell therapy as the most recent treatment.
Study Design and Methods:
This study (NCT05179603) is an open-label, non-randomized, multi-cohort, and multi-center trial. Enrollment is ongoing for both sub-studies (targeting 25 patients per sub-study). Participating countries are Argentina, Canada, Chile, France, Israel, Italy, Mexico, Spain, UK, and US. Key inclusion criteria include age of ≥12 years old, relapsed or refractory disease, at least one measurable lesion per Lugano response criteria 2014, and adequate organ function. Key exclusion criteria include ECOG of ≥2 (≥16 years old)/Lansky Scale ≤60% (<16 years old), active brain metastasis, life expectancy ≤3 months and history of solid organ transplant.
The cHL sub-study enrolls patients who have received at least 2 prior lines of systemic therapy to test SAR444245 24 ug/kg in combination with pembrolizumab 200 mg every 3 weeks. The DLBCL sub-study enrolls patients who have received at least 2 prior lines of systemic therapy to test SAR444245 24 ug/kg every 2 weeks. CD19 directed CAR-T cell therapy must be the most recent treatment administered in the past 3 months with stable disease or progressive disease as the best overall response. All CAR-T therapy related adverse events must have resolved to grade 1 or less.
A safety run-in in each sub-study including at least 6 dose-limiting toxicity (DLT) evaluable patients is designed to confirm the study medication dose for the remaining patients. The dose may be reduced based on the occurrence of DLT and overall safety profile of the patients recruited in the safety run-in. Patients will receive study treatment until disease progression, unacceptable toxicity, or completion of 2 years of treatment.
The cHL sub-study primary endpoint is the complete response rate. The DLBCL sub-study primary endpoint is the objective response rate. Both primary endpoints are based on Lugano response criteria 2014. The main secondary endpoints include safety and other efficacy assessments.
Disclosures
Berkovits:Astrazeneca: Honoraria; Pfizer: Honoraria; Janssen: Other: Support for attending meetings and/or travel. Rojas:AstraZeneca: Other: Personal Fees; Novartis: Other: Personal Fees; Janssen: Other: Personal Fees; Roche: Other: Personal Fees. Gazitua:Janssen: Other: Support for attending meetings and/or travel; Abbvie: Other: Support for attending meetings and/or travel; Roche: Other: Support for attending meetings and/or travel. Sureda:Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria; Pierre Fabre: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Jannsen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; MSD: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding. Saleem:Sanofi: Current Employment, Current equity holder in publicly-traded company. Meng:Sanofi: Current Employment, Current equity holder in publicly-traded company. Xu:Sanofi: Current Employment, Current equity holder in publicly-traded company. Streit:Sanofi: Current Employment, Current equity holder in publicly-traded company. Barboux:IT&M stats: Current Employment. Ahmed:Myeloid Therapeutics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Chimagen: Consultancy, Research Funding; Xencor: Research Funding; Tessa Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Seagen: Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
