Novel Epidrugs May Require Dose Fine Tuning in Phase I Trials

The risk of a patient experiencing a haemotologic toxicity during or after the first cycle of treatment with an epigenetic drug varies according to the patient’s disease type, researchers reported at the TAT 2019 – International Congress on Targeted Anticancer Therapies in Paris, France.

A research team from the Institute Gustave Roussy investigated whether more precise evaluation may be required for epigenetic drugs (epidrugs) in order to determine the recommended phase II dose.

Laura Leroy of the Institut Gustave Roussy in Villejuif, France noted that targeting the epigenome has been a successful approach in haematological malignancies and has also shown promising activity for solid tumours in phase I trials. Many of these agents are evaluated as first-in-class, first-in-human compounds and accurate knowledge of their safety profile and toxicity management is essential for appropriate phase II dose recommendation.

This retrospective analysis of all patients with haematologic or solid tumours who were enrolled in at least one phase I epidrug trial at the Gustave Roussy Drug Development Department comprised baseline patient characteristics, information regarding treatment-related adverse events (AEs), including type, grade, date of occurrence, duration, and resolution, as well as toxicity management with medication and/or dose modification, and patient outcome.

Data from 243 patients were collected, including 43.6% of patients with haematologic cancer, 23.1% with non-Hodgkin lymphoma (NHL), and 33.3% of patients with not-NHL solid tumours. The patients had participated in one of 15 phase I epidrug monotherapy trials from January 2010 to March 2017. The majority (62%) of patients were male, with a median age of 65 years. 

Most toxicity occurs early in treatment

The 243 patients received treatment with an epidrug for a median duration of 119 days. A total of 1980 treatment cycles and 335 AEs were assessed.

Thirty-five percent of all grade AEs occurred during cycle 1; of these, 64 patients had grade 1 and 2 AEs and 54 patients had grade 3 and 4 AEs. Most (65%) of the AEs occurred after cycle 1, the dose limiting toxicity (DLT) period.  Of these, 114 AEs were grade 1 and 2, while 103 AEs were grade 3 to 4.

DLT occurred in 10 (4%) patients. Fifteen percent of patients required dose reduction after a median treatment duration of 21 days. Temporary treatment interruption for toxicity was necessary for 21% and definitive treatment interruption occurred in 9% of patients. The majority (73,4%) of DLTs occurred after treatment cycle 1.

The risk of a haemotologic toxicity is highest in patients with NHL

Fifty-eight percent of the AEs were haematological toxicities. Patients with haematologic malignancy had a risk of grade 3-4 toxicity of 15% during cycle 1 and a risk of 11% after cycle 1.

In patients with solid tumours, the risk of grade 3-4 toxicity during and after cycle 1 was 12% and 18% for patients with solid tumours, respectively.  In patients with NHL, the risk was 29% and 24% during and after cycle 1, respectively.

Conclusions

The authors pointed out that epidrugs have shown efficacy for patients with haematologic malignancies and activity in patients with solid tumours in phase I trials, resulting in several first-in-class, first-in-human selective compounds now being evaluated in phase I trials. However, findings from this analysis from a single institution show that 65% of high-grade AEs occur after cycle 1 during phase I trials and just 42% of toxicities are non-haematologic.

The risk of haemotologic toxicity was especially pronounced in patients with NHL, who showed a 2-fold higher risk than patients with solid tumours or patients with not-NHL haematological malignancies.  

After analysis of 335 AEs, the majority of severe grade 3 or 4 AEs occurred in cycle 1, prompting the investigators to advise that the dose recommendation process may require fine-tuning for each patient population.

They concluded that epidrugs have distinct toxicity profiles according to each cancer type that require specific attention during the development process and in the dose determining phase.

Reference

10P – Leroy L, Satar T, Baldini C, et al. Safety profile of epigenetic therapies in early phase trials: Do epidrugs deserve specific drug development processes?