Novartis is conducting a Phase I clinical trial (NCT04857372) to investigate the safety, tolerability, pharmacokinetics, and preliminary efficacy of IAG933 in patients with advanced solid tumors. IAG933 is a TEAD inhibitor, targeting tumors with specific genetic alterations.
Study Design and Patient Population
The study employs a dose escalation and expansion design. The dose escalation phase includes patients with advanced mesothelioma or other solid tumors harboring loss-of-function NF2/LATS1/LATS2 genetic alterations or functional YAP/TAZ fusions. The dose expansion phase enrolls patients into different treatment groups based on their specific tumor type and genetic profiles, including those with advanced mesothelioma, NF2-mutated solid tumors, and YAP/TAZ-fusion-positive solid tumors.
Key inclusion criteria mandate that patients have failed, are intolerant of, or are ineligible for standard therapies, or have no available standard treatment options. Patients must also have measurable lesions and be candidates for tumor biopsies at screening, baseline, and during therapy. Exclusion criteria include recent anticancer therapies, significant cardiac or renal dysfunction, and active infections.
Treatment and Endpoints
IAG933 is administered to assess its impact on tumor response in these genetically defined cancers. The study's primary endpoints focus on safety and tolerability, while secondary endpoints evaluate pharmacokinetic parameters and preliminary antitumor activity based on mRECIST v1.1, RECIST v1.1, or RANO criteria, depending on the tumor type.
Rationale for TEAD Inhibition
The rationale for using a TEAD inhibitor like IAG933 stems from the role of the Hippo pathway in tumor development. Disruptions in NF2, LATS1/2, or the presence of YAP/TAZ fusions can lead to aberrant activation of TEAD transcription factors, driving uncontrolled cell growth. By inhibiting TEAD, IAG933 aims to suppress this oncogenic signaling pathway in tumors where it is inappropriately activated.
Clinical Significance
This trial addresses a critical unmet need for patients with advanced solid tumors who have limited treatment options. The study's focus on genetically defined subgroups allows for a more targeted approach, potentially improving outcomes for patients whose tumors are driven by specific Hippo pathway alterations. The inclusion of on-treatment biopsies will provide valuable insights into the drug's mechanism of action and potential biomarkers for response.
