Abstract CT134: Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic study of oral TP-0184, an activin receptor-like kinase-2 (ALK2) inhibitor, in patients (pts) with advanced solid tumors (ASTs)
Authors: Baranda Joaquina , Gordon Michael S. , Parikh Aparna R. , Yang Huyuan , Pennock Gregory K. , Komarnitsky Philip , Beg Muhammad S. 
Published: June 2022

Abstract
Background: ALK2 is mutated in several cancers, including melanoma and endometrial, colorectal, bladder, and breast cancers. TP-0184 is an orally delivered ALK2 inhibitor, part of the transforming growth factor beta receptor superfamily of serine/threonine kinases, expected to reduce tumor growth in ALK2-dependent cancers. Safety, PK, and preliminary anti-tumor activity from a phase 1 study of TP-0184 in pts with ASTs (NCT03429218) are presented.
Methods: Pts with metastatic/progressive ASTs refractory to/intolerant of established therapy received oral TP-0184. Escalating doses were evaluated via a 3+3 design, starting with 30 mg/day (d) for 21/28 d. However, preliminary time-to-steady-state PK data (data cutoff: March 31, 2021) suggested a half-life of ~3-5 d. Given the estimated longer half-life (compared to available preclinical data), the protocol was amended to a dose of 60 mg once a wk (QW) for 4 wks. All pts continued on the same regimen until disease progression or unacceptable toxicity. Primary objectives: maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives: PK, antitumor activity, and recommended phase 2 dose.
Results: At data cutoff (May 27, 2021), 24 pts were treated. Mean age was 63.1 (range 34.1-83.4) y, 83.3% were female, and 75.0% had an ECOG PS of 1. Most common tumor types (≥2 pts) were colorectal (n=5); pancreatic (n=3); and lung, ovarian, and peritoneal (n=2 each). Dose escalation reached 125 mg QW (not expanded due to lack of meaningful antitumor response at 125 mg QW and study closure). No pt experienced a DLT; MTD was not reached. All pts experienced a treatment-emergent adverse event (TEAE), most commonly nausea (50%); 14 (58.3%) pts experienced a Grade 3-4 TEAE, most commonly anemia (n=3); abdominal pain, pulmonary embolism, nausea, and vomiting (n=2 each). Eight (33.3%) pts experienced a serious adverse event and 1 pt in the 60-mg QD group died during study due to disease progression, considered unrelated to treatment. Best response was stable disease in 7 (30.4%) and progressive disease in 15 (65.2%) pts; not done (n=1, 4.3%). No partial responses were observed. Preliminary PK data (data cutoff: March 31, 2021) from the weekly dosing cohorts indicated dose-related increases in exposure (maximum concentration [Cmax]) from 60 mg (Day [D] 1=20.9 [standard deviation (SD) 12.9] ng/mL; D21=32.3 [SD 26.9] ng/mL) to 125 mg (D1=45.3 [SD 27.8] ng/mL; D21=144.0 ng/mL [SD not available]), except for a decrease in mean Cmax on D1 from 90 mg to 125 mg (data not shown). Drug accumulation was observed with QW dosing but to a lesser extent than daily dosing.
Conclusions: Preliminary data suggest that TP-0184 is tolerated as monotherapy at doses up to 125 mg QW; MTD was not reached. A study in pts with myelodysplastic syndromes is ongoing.
Citation Format: Joaquina Baranda, Michael S. Gordon, Aparna R. Parikh, Huyuan Yang, Gregory K. Pennock, Philip Komarnitsky, Muhammad S. Beg. Phase 1, first-in-human, dose-escalation, safety, pharmacokinetic (PK), and pharmacodynamic study of oral TP-0184, an activin receptor-like kinase-2 (ALK2) inhibitor, in patients (pts) with advanced solid tumors (ASTs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT134.