Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Abstract

Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway.Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/ feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1.Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade !3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n ¼ 4) and fatigue (n ¼ 3) were most common. Oral absorption was fairly rapid; median T max was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentrationtime curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors).Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling.

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

“…Lower incidences of grade 3/4 AEs, SAEs and AEs leading to discontinuation were observed with 200 mg vs. 800 mg. The majority of the most common AEs were generally grade 1 or 2 and were similar to those reported with other HPIs10, 11, 12, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39; muscle‐related AEs and the increase in CK that can accompany these AEs are thought to be a class effect of HPIs 11, 12, 30, 31, 35, 39. Muscle‐related AEs were effectively managed with dose adjustments or interruptions.…”

The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels

“…This supports the idea that Gpr175 has a permissive rather than instructive role in Hh signaling, in other words acts as a booster of Smo activity in cells requiring high levels of signaling rather than being an essential component. In this respect, it is interesting to note that GPR175 is up-regulated in certain Hh ligand-dependent cancers (data not shown), such as colorectal cancers that are clinically unresponsive to Smo inhibitors (61,62). Because GPR175 depletion inhibited Hh signaling in medulloblastoma cells (Fig.…”

Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors

“…Several other SMO inhibitors have been developed and tested in clinical trials [18][19][20]. As with vismodegib and sonidegib, single-agent activity was limited to BCC and medulloblastoma, two tumor types with known mutations (mainly PATCH1 and SMO) leading to ligand-independent Hh pathway activation.…”