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First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with
Timothy A Yap1, Maria Vieito2, Capucine Baldini3
1Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas. tyap@mdanderson.org.
The novel TGFβ inhibitor LY3200882 showed promising safety and antitumor activity in advanced cancers. Pancreatic cancer patients demonstrated significant disease control with LY3200882 combination therapy.
Area of Science:
- Oncology
- Translational Medicine
- Pharmacology
Background:
- Transforming growth factor beta (TGFβ) signaling is implicated in cancer progression.
- LY3200882 is a novel, selective, next-generation TGFβ receptor type-1 small molecule inhibitor with promising preclinical data.
Purpose of the Study:
- To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882.
- To determine the recommended phase II dose (RP2D) of LY3200882.
- To assess LY3200882 as monotherapy and in combination with other anticancer agents in patients with advanced cancer.
Main Methods:
- A phase I multicenter study (NCT02937272) involving dose escalation and expansion cohorts.
- Patients received oral LY3200882 as monotherapy (grade 4 glioma) or in combination therapies (solid tumors, pancreatic cancer, head and neck squamous cell cancer).
- Combination regimens included LY3200882 with PD-L1 inhibitor LY3300054, or with gemcitabine and nab-paclitaxel, or with cisplatin and radiation.
Main Results:
- 139 patients with advanced cancer were treated. Most experienced treatment-emergent adverse events (TEAEs), with 39.6% related to LY3200882. Grade 3 toxicities were limited to combination arms.
- RP2Ds for LY3200882 monotherapy were established: 50 mg BID (2-weeks-on/2-weeks-off) and 35 mg BID (3-weeks-on/1-week-off).
- Durable partial responses (PR) were observed in 4 patients with grade 4 glioma. In treatment-naïve advanced pancreatic cancer, the combination of LY3200882, gemcitabine, and nab-paclitaxel achieved a 75% disease-control rate (6 PR, 3 stable disease).
Conclusions:
- LY3200882, as monotherapy and in combination, was safe and well-tolerated.
- Preliminary antitumor activity was observed, particularly in advanced pancreatic cancer.
- Further studies evaluating LY3200882 in combination with gemcitabine and nab-paclitaxel for advanced pancreatic cancer are warranted.
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