A phase 1/2 study of STP938, a first-in-class inhibitor of CTP synthase 1, in patients with relapsed/refractory B or T cell lymphoma.

TPS7591 Background: The rate limiting step in de novo pyrimidine synthesis is catalyzed by two homologous enzymes, CTPS1 and CTPS2. CTPS1 is essential for lymphocyte proliferation, whereas CTPS2 is sufficient in non-haemopoietic cells. STP938 is a first in class oral CTPS1 inhibitor showing > 1,300-fold selectivity over CTPS2. In preclinical studies, STP938 induced death of cancer cells by apoptosis at nanomolar concentrations, and inhibited tumor growth in in vivo models of hematological malignancies. Methods: The study employs a seamless dose escalation, dose expansion design. The phase 1 dose escalation follows a standard 3+3 approach. Intra-patient dose escalation will be permitted. The recommended phase 2 dose (RP2D) will be nominated based on safety, target engagement and early signs of efficacy. An additional six patients will be treated at the RP2D with a preliminary assessment of food effect. Key phase 1 endpoints are safety and tolerability. Key phase 2 endpoints are objective response rate and duration of response. The study is open to adult patients following at least 2 prior lines of therapy who have no treatment options known to provide clinical benefit. The phase 1 study is recruiting patients with B or T cell lymphoma; the phase 2 study will be limited to cohorts of patients with specific lymphoma subtypes, which may include T cell lymphoma (peripheral or cutaneous), mantle cell lymphoma, indolent B cell lymphoma and diffuse large B cell lymphoma. Standard exclusion criteria apply; patients with ECOG performance score > 2 or known CNS involvement by lymphoma are not eligible. The phase 2 study will follow a Simon two-stage design with an interim analysis for futility based on predefined, lymphoma subtype specific response rates. In the case of STP938 showing promising efficacy, provision is included in the protocol to expand a cohort using an adaptive approach based on early efficacy signals (Mehta and Pocock, 2011). Target engagement is assessed by measuring cytokine release (TNFα, IFNγ, IL2, IL8) from ex vivo stimulated patient T cells. Exploratory studies include pre- and on-treatment lymphoma biopsies to assess biomarkers of response and mechanism of action. Tumor genomics will be assessed by sequencing of circulating tumor DNA prior to treatment and at disease progression using a bespoke genomic assay designed to elucidate biomarkers of response and understand mechanisms of resistance. The phase 1 study (NCT05463263) opened to enrolment in the US and UK in September 2022. No dose limiting toxicities were observed in the first cohort of 3 patients. The phase 2 study will include additional centers in France. Clinical trial information: NCT05463263 .