First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL)

Summary

Arginine methylation mediated by protein arginine methyl-transferases (PRMTs) is an important post-translational modification of proteins involved in a diverse range of cellular processes. Misregulation and overexpression of PRMT1 (a type I PRMT) has been associated with a number of solid and hematopoietic cancers. GSK3368715 leads to inhibition of tumor cell growth across tumor types with cytotoxic response observed in lymphoma, acute myeloid leukemia (AML) and a subset of solid tumor cell lines. This study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), food effect and preliminary clinical activity of GSK33368715 in participants with relapsed/refractory DLBCL and selected solid tumors with frequent methyl-thioadenosine phosphorylase (MTAP)-deficiency. The study will consist of two parts. In Part 1 (Dose Escalation) escalating doses of GSK3368715 will be evaluated and recommended phase 2 dose (RP2D) will be established in participants with selected solid relapsed/refractory tumors. Once a RP2D is identified, a food effect sub-study will be initiated to determine the effect of a high-fat, high calorie meal on the bioavailability of GSK3368715. In Part 2 (Dose Expansion), this RP2D will be further investigated in two expansion cohorts; participants with DLBCL (Expansion Cohort 2A) and relapsed/refractory solid tumors including pancreatic, bladder, and non-small cell lung cancer (NSCLC)(Expansion Cohort 2B). The study includes a screening period, an intervention period and follow up.

Timeline

Start

2018-10-22

Primary completion

2021-03-04

Completion

2021-03-04

Outcome

Outcome not reported

Stopped: “Overall benefit-risk profile did not support continuation of the study”

Publications

• El-Khoueiry AB, Clarke J, Neff T, Crossman T, Ratia N, Rathi C, Noto P, Tarkar A, Garrido-Laguna I, Calvo E, Rodon J, Tran B, O'Dwyer PJ, Cuker A, Abdul Razak AR. Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors. Br J Cancer. 2023 Aug;129(2):309-317. doi: 10.1038/s41416-023-02276-0. Epub 2023 May 26.

Drugs

Indications