A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers

Abstract

ObjectiveWee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers.MethodsA multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45–50 Gy in 1.8–2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m2and adavosertib 100 mg/m2on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy.ResultsTen patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level −1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free.ConclusionThe recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

“…As PKMYT1, but not WEE1, is more important for G2/M transition during checkpoint recovery [207] its inhibitors could be important for a number of combinational therapies aimed at RS. and rhabdomyosarcoma [194,195,[208][209][210][211][212][213][214][215] Phase 1 (34 trials, including 6 terminated and 1 withdrawn) HNSCC, uterine cancers, TNBC, pancreatic cancer, acute myeloid leukemia, glioblastoma [192,193,[216][217][218][219][220][221][222][223][224][225][226][227][228]…”

Targeting WEE1 Kinase in Gynecological Malignancies

“…[20][21][22][23][24] Current literature reports the antitumor effects of WEE1i in a variety of in vitro and in vivo tumor models, either alone or in combination with other DNA-damaging modalities. 14,18,19,[25][26][27][28][29][30][31][32][33][34]…”

“…In the absence of intolerable AEs or disease progression, treatment is continued for up to five weeks. According to the preliminary results that were recently published 34 , ten patients were enrolled (nine locally advanced CC and one EC), and the recommended phase II dose could not be determined due to clinical toxicity and early trial closure. The overall response rate at 4 months was 71.4%, including four complete responses.…”

“…At 2 years follow-up, 86% of patients were alive and progression-free. 34 While overlap toxicity is a challenge, the preliminary efficacy of Adavosertib in conjunction with chemoradiation is encouraging.…”

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

“…As PKMYT1, but not WEE1, is more important for G2/M transition during checkpoint recovery [207] its inhibitors could be important for a number of combinational therapies aimed at RS. and rhabdomyosarcoma [194,195,[208][209][210][211][212][213][214][215] Phase 1 (34 trials, including 6 terminated and 1 withdrawn) HNSCC, uterine cancers, TNBC, pancreatic cancer, acute myeloid leukemia, glioblastoma [192,193,[216][217][218][219][220][221][222][223][224][225][226][227][228]…”