AZD1775, a small-molecule, WEE1-targeting TKI, significantly shrunk tumors when administered in combination with cisplatin and docetaxel in a phase I trial.
A small phase I dose-finding study in 10 patients with advanced head and neck cancer has shown that adavosertib (also known as AZD1775) administered in combination with cisplatin and docetaxel, significantly shrunk tumors in 9 of the patients enrolled. Adavosertib, a small-molecule inhibitor of the tyrosine kinase WEE1, has potential antineoplastic sensitizing activity.
The late Eduardo MÃ©ndez, MD, and colleagues from Fred Hutchinson Cancer Center, Seattle, Wash., published the study results in Clinical Cancer Research. In the trial, the experimental TKI–chemotherapy combination was administered to 10 people with advanced head and neck cancer who were either ineligible for surgery or had tumors that, if treated surgically, would have resulted in significant disfigurement.
The majority (about two-thirds) of head and neck cancer tumors carry p53 mutations; as a result, they lack the G1 checkpoint (which is mainly regulated by p53). Instead, these malignant cells repair damaged DNA through the G2 checkpoint.
As explained by the National Cancer Institute it its drug thesaurus, inhibition of WEE1 activity by adavosertib prevents CDC2 phosphorylation and impairs the G2 DNA damage checkpoint. This interference with G2 checkpoint function may make p53-deficient tumor cells more vulnerable to chemotherapeutic agents targeting DNA, thereby enhancing the cytotoxic effect of treatment.
The open-label study by MÃ©ndez et al enrolled 10 patients with stage III/IVB borderline-resectable or unresectable head and neck cancer. All patients were candidates for definitive chemoradiation. The researchers used a 3+3 dose-escalation design. AZD1775 was administered orally twice a day over 2.5 days during the first week, and then was given in combination with cisplatin (at 25 mg/m2) and docetaxel (at 35 mg/m2) for 3 weeks. Adverse events were the primary outcome measure, to establish the maximum tolerated dose (MTD). Response, pharmacokinetics, pharmacodynamics, and genomic data were secondary outcome measures.
The AZD1775 MTD was determined to be 150 mg orally twice daily for 2.5 days. Responses as measured by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 were seen in 5 patients, and 3 additional responders were identified following histological adjustment. Grade 3 diarrhea was the only drug-limiting toxicity.
MÃ©ndez and colleagues concluded that combination therapy with AZD1775, cisplatin, and docetaxel is safe and tolerable, “with promising antitumor efficacy…meriting further investigation at the recommended phase 2 dose.”
As a news release from Fred Hutchinson cancer center pointed out, when this clinical trial was designed, the investigators also permitted patients without p53 mutations to enroll if their cancer had been triggered by HPV infection, which, similar to mutation, also inactivates p53. In fact, 3 trial participants who had a good response to the AZD1775–chemotherapy combination had HPV-positive tumors that did not carry p53 mutations.
Senior author Laura Q.M. Chow, MD, commented in the news release that “[t]he interesting thing is [that the combination therapy] had more of an effect than we expected. People actually had dramatic shrinkage of their cancers to the point that they didn’t have cancer left at time of surgery.”
This clinical trial was funded by the National Institutes of Health; the American Cancer Society; philanthropic donations to Fred Hutchinson Cancer Center; the Seattle Cancer Care Alliance; and AstraZeneca.