Abstract PO1-20-04: STX-478-101: A phase 1/2, first-in-human study of STX-478 monotherapy or in combination with fulvestrant in patients with breast cancer or other advanced solid tumors (trial in progress)
Authors: Montero Alberto , Orr Douglas , Munster Pamela , LoRusso Patricia , Jhaveri Komal , Pluard Timothy , Winer Ira , Streit Michael , Patterson Monica , Roberts Simon , Corsi-Travali Stefani , Ewert Courtney , Juric Dejan 
Published: May 2024

Abstract
Background: The phosphoinositide 3-kinase-alpha (PI3Kα)/AKT/mTOR pathway is one of the major pathways in oncogenesis. PI3Kα alterations are especially prevalent in breast, gynecological, and head and neck squamous cell carcinomas. PI3Kα oncogenic mutations are highly enriched for kinase (H1047X) and helical (E542K, E545K) domain hotspots. The therapeutic potential of isoform-selective PI3Kα inhibition in PI3Kα-mutant cancers was established with alpelisib, which shows equipotent activity against both wild-type (WT) and mutant PI3Kα. However, alpelisib use is limited by toxicities induced by WT PI3Kα inhibition, e.g. hyperglycemia and mucositis. This suggests that mutant-selective PI3Kα inhibitors have the potential to improve efficacy while sparing WT-related toxicity. STX-478 is an investigational allosteric, mutant-selective PI3Kα inhibitor. Preclinical testing in human breast cancer xenografts bearing helical- or kinase-domain mutant PI3Kα demonstrated that STX-478 monotherapy and combinations with fulvestrant and/or CDK4/6 inhibitors provided robust efficacy without the metabolic dysfunction observed with alpelisib.
Trial Design: This first-in-human, multicenter, phase 1/2 study (NCT05768139) evaluates the optimal dosing, safety, and preliminary efficacy of STX-478 as monotherapy in patients with locally-advanced or metastatic HR+/HER2− breast cancer or other solid tumor types with PI3Kα H1047X mutations, other kinase domain mutations, or helical domain mutations (Part 1), and STX-478 in combination with fulvestrant in patients with locally-advanced or metastatic HR+/HER2− breast cancer with PI3Kα H1047X or other kinase domain mutations (Part 2). Part 1 comprises 2 subparts (Table 1) to define the optimally biologically active dose (OBD) and maximum tolerated dose (MTD) in Part 1.1, and recommended phase 2 dose (RP2D) of STX-478 monotherapy in Part 1.2. At the conclusion of each dose-level in Part 1.1 (3 + 3 design), a backfill cohort will be initiated in patients with HR+/HER2− breast cancer with PI3Kα H1047X mutations or other kinase domain mutations, who will receive STX-478 at the determined safe dose. Part 2 comprises two subparts (Table 2) to define RP2D and assess the initial efficacy of STX-478 in combination with fulvestrant in patients with HR+/HER2− breast cancer expressing PI3Kα H1047X or other kinase domain mutations.
Key Eligibility Criteria: Adults with a PI3Kα-mutant advanced or refractory solid tumor malignancy that is metastatic or locally advanced and unresectable, ECOG performance status score of 0–1, and no prior PI3K/AKT/mTOR inhibitor(s) use (except with prior intolerance) are eligible. Individuals with diabetes mellitus type 1 or uncontrolled diabetes mellitus type 2 are excluded. Cohort-specific eligibility criteria are provided in Tables 1 and 2.
Endpoints: Efficacy, safety, pharmacokinetics, pharmacodynamics, patient-reported quality of life, and biomarkers (e.g., glucose metabolism, circulating tumor DNA) will be assessed.
Trial Status: Recruitment opened April 2023 in the US and is ongoing, with potential for ex-US site expansion. Contact clinicaltrials@scorpiontx.com for additional information.
Table 1. Part 1 Dose Escalation, RP2D Selection, and RP2D Expansion (STX-478 Monotherapy)
Table 2. Part 2 RP2D Selection and Expansion (STX-478 + Fulvestrant Combination Therapy)
Citation Format: Alberto Montero, Douglas Orr, Pamela Munster, Patricia LoRusso, Komal Jhaveri, Timothy Pluard, Ira Winer, Michael Streit, Monica Patterson, Simon Roberts, Stefani Corsi-Travali, Courtney Ewert, Dejan Juric. STX-478-101: A phase 1/2, first-in-human study of STX-478 monotherapy or in combination with fulvestrant in patients with breast cancer or other advanced solid tumors (trial in progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-04.