Phase 1 Pancreatic Cancer Trial Identifies Effective Combination Treatment

Pancreatic cancer is among the deadliest cancers, with 5-year survival rates below 35%. However, a phase 1 clinical trial testing a new drug in this condition—an inhibitor designed to block an enzyme called Wee1—has shown promising results, suggesting a need for additional investigation.

The trial results, published in the Journal of Clinical Oncology, included 34 patients with locally advanced pancreatic cancer who received four 21-day cycles of gemcitabine with the inhibitor AZD1775, or adavosertib. The second and third cycles were administered with radiation; cycles 5 to 8 were optional.

“AZD1775 was dose-escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation,” noted the authors. “Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues.”

The results revealed that 24% of patients experienced a dose-limiting toxicity, such as anorexia, nausea, or fatigue. Additionally, the researchers found that the median overall survival for all patients was 21.7 months, and the median progression-free survival was 9.4 months. Samples from hair follicles demonstrated Wee1 inhibition had decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase 2 dose, according to the results.

Gemcitabine has been a therapy for pancreatic cancer for more than a decade, and these results show that the therapy will be effective when in combination with radiation. The researchers suggested that the recommended phase 2 dose of AZD1775 was 150 mg/d.

"If we can disable the DNA damage response in pancreatic cancer cells, it might eliminate treatment resistance and sensitize the cancer to the effects of both radiation and chemotherapy," lead study author Kyle Cuneo, MD, associate professor of radiation oncology at Michigan Medicine, said in a statement.

Despite the efficacy of the treatment in the trial, the researchers emphasized the need for further studies in order to further investigate the treatment combination.

"If we're ever going to cure pancreatic cancer, we're going to need effective systemic treatment as well as local therapy. Our data suggests that AZD1775 can do both," concluded senior study author Ted Lawrence, MD, PhD, Isadore Lampe Professor and chair of radiation oncology at Michigan Medicine.

Reference

Cuneo K, Morgan M, Sahai V, et al. Dose escalation trial of the Wee1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer [published online August 9, 2019]. J Clin Oncol. doi. org/10.1200/JCO.19. 00730.