Toxicity doesn't stop Incyte

Despite ongoing setbacks in the phase 1 trial of Incyte's KRAS G12D inhibitor INCB161734, which remains on hold in several European countries, the company has moved it into pivotal development. 

The first pivotal trial, Dawn-03, has appeared on clinicaltrials.gov. The move is notable not only because it shows a leap straight from phase 1 to phase 3, but also because patient recruitment is already under way, even as Incyte remains silent about the ongoing phase 1 problems. 

And that’s not the only issue Incyte has faced with its KRAS G12D inhibitors in recent months, as an apparent follow-up asset, INCB186748, also appears to have prematurely concluded its first-in-human trial. According to clinicatrials.gov, the study is marked as “active, not recruiting,” with only 30 subjects enrolled; the initial recruitment target was 308 patients.

Dawn-03 is designed to evaluate INCB161734 in combination with chemotherapy, versus chemo alone, as a first-line treatment for patients with KRAS G12D-mutant pancreatic cancer. The primary endpoints are overall survival, progression-free survival and overall response rate.

1.2g dose? 

Notably, the new registry entry doesn't specify the dose that will be used in the pivotal study. Presumably this will be the 1.2g daily dose previously identified as optimal by Incyte, though this is the same dose that prompted authorities in Spain, Belgium, Italy and France to halt the phase 1 trial.

It also remains unclear whether any of the patients who experienced serious toxicity in phase 1 had pancreatic cancer specifically. The phase 1 study enrolled patients with a diverse range of solid tumours, including pancreatic ductal adenocarcinoma, colorectal cancer, non-small cell lung cancer, ovarian cancer, and others. 

With Incyte still withholding public comment on the nature of these adverse events, questions continue regarding which tumour types or patient subgroups might be at highest risk, and what additional precautions, if any, will be implemented in the phase 3 setting. 

The clinical hold was triggered by a case of grade 5 pneumonitis in a patient. After the fatality, Incyte reviewed the approximately 300 other enrolled patients and identified three additional cases of confirmed or suspected pneumonitis, all linked to the 1.2g dose. Notably, three of the four cases occurred in cohorts receiving the combination with chemotherapy, the same regimen now under investigation in the Dawn-03 trial. 

Ongoing clinical trials evaluating INCB161734

Source: OncologyPipeline.