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

Background: Chemotherapy-induced inhibition of DNA synthesis has proven efficacy in the treatment of lymphoma. Selective targeting of DNA synthesis has the potential to surpass this efficacy by maximizing pathway inhibition whilst avoiding the dose limiting toxicities of chemotherapy. The rate limiting step in de novo pyrimidine synthesis is catalysed by two homologous enzymes, CTPS1 and CTPS2. CTPS1 is essential for lymphocyte proliferation, whereas CTPS2 is sufficient in non-haemopoietic cells, raising expectations of a therapeutic window for selective CTPS1 inhibition. STP938 is a first in class oral CTPS1 inhibitor showing >1300-fold selectivity over CTPS2. In preclinical studies, STP938 induced death of cancer cells by apoptosis at nanomolar concentrations, and inhibited tumour growth in in vivo models of haematological 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 & 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. Tumour genomics will be assessed by sequencing of circulating tumour 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 research was funded by: Step Pharma SAS Keywords: aggressive B-cell non-Hodgkin lymphoma, aggressive T-cell non-Hodgkin lymphoma, molecular targeted therapies Conflicts of interests pertinent to the abstract. M. Ahearne Research funding: Step Pharma Educational grants: Medscape K. Linton Consultant or advisory role Abbvie, Genmab, Kite/Gilead, BeiGene, Bristol-Myers Squibb, Celgene, Roche Research funding: Abbvie, Genmab, Kite/Gilead, BeiGene, Bristol-Myers Squibb, Celgene, Roche, Nurix, CellCentric, MorphoSys, Jenssen, ADC Therapeutics, MSD, Viracta Therapeutics, Regeneron, Step Pharma, AstraZeneca Educational grants: Celgene C. P. Fox Consultant or advisory role Abbvie, Gilead, Roche, Takeda, Atara Biotherapeutics, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Genmab, Lilly, MorphoSys/Incyte, Ono Pharmaceutical Research funding: BeiGene Educational grants: Roche D. Lewis Consultant or advisory role Janssen, Kite/Gilead, Beigene Educational grants: Kite M. Patel Consultant or advisory role Olema Pharmaceuticals, ION Pharma, Janssen, Acerta Pharma, ADC Therapeutics, Agenus, Aileron Therapeutics, AstraZeneca, BioNTech, Boehringer Ingelheim, Celgene, CicloMed, Clovis, Cyteir, Daiichi Sankyo, Lilly, Evelo Therapeutics, Genetech/Roche, Gilead, GlaxoSmithKline, H3 Biomedicine, Hengrui Therapeutics, Hutchison MediPharma, Jacobio, Accutar Biotech, Adagene, Artios, Astellas, Bayer, Bicycle Therapeutics, BioTheryX, Black Diamond Therapeutics, Blueprint Medicines, Compugen, Cullinan Oncology, Erasca, Inc, IgM Biosciences, Immune-Onc Therapeutics, Immunitas, Immunogen, Janssen, Jazz Pharmaceuticals, Klus Pharma, Kymab, Loxo, LSK BioPharma, Lycera, MabSpace Biosciences, Macrogenics, Merck, Millennium, Mirati Therapeutics, Moderna Therapeutics, NGM Biopharmaceuticals, Novartis, nurix, Olema Oncology, ORIC Pharmaceuticals, Pfizer, Pionyr, Prelude Therapeutics, Puretech, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Samumed, Seven and Eight Biopharmaceuticals, Silicon Therapeutics, Step Pharma, Syndax, Synthorx, Taiho Pharmaceutical, TeneoBio, Tesaro, TopAlliance BioSciences Inc, Treadwell Therapeutics, Vigeo Therapeutics, Xencor, Zymeworks M. Higgins Employment or leadership position: Step Pharma Stock ownership: Step Pharma B. Schwartz Employment or leadership position: Step Pharma, Enlivex Therapeutics Ltd, Cyclacel, Infinity Pharmaceuticals Stock ownership: Step Pharma, Enlivex Therapeutics Ltd, Cyclacel, Infinity Pharmaceuticals P. A. Beer Employment or leadership position: Step Pharma Stock ownership: Step Pharma