Safety, Antitumor Activity, and Biomarker Analysis in a Phase I Trial of the Once-daily Wee1 Inhibitor Adavosertib (AZD1775) in Patients with Advanced Solid Tumors

Abstract

The Wee1 kinase inhibitor adavosertib abrogates cell cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase 2 dose (RPh2D). Here, we report results for once-daily adavosertib.Patients and Methods: A 3 + 3 dose escalation design was used, with adavosertib given once daily on days 1-5 and 8-12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15-phosphorylated Cdk1/2 [pY15-Cdk]), were assessed in paired tumor biopsies.Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers.Results: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematological; dose-limiting toxicities were grade 4 hematological toxicity and grade 3 fatigue.The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses (PR): 4 ovarian, 2 endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in 4 of 8 patients, suggesting target rebound during the day 5-8 dosing break. One patient who progressed rapidly had a tumor WEE1 mutation and potentially compensatory PKMYT1 overexpression.Baseline CCNE1 overexpression occurred in both of 2 responding patients, only 1 of whom had CCNE1 amplification, and in 0 of 3 non-responding patients. Conclusions:We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including 2 with baseline CCNE1 mRNA overexpression. Future studies will determine whether CCNE1 overexpression is a predictive biomarker for adavosertib.

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

“…Neutrophil count decreases were also observed in randomized phase III trials of PARP inhibitors, especially with niraparib and talazoparib, but G ≥ 3 events were not frequent and febrile neutropenia was rare [ 25 , 26 ]. Similar results emerged in early phase trials with the WEE1 inhibitor adavosertib [ 40 , 41 , 42 , 52 ], while neutropenia was common and often severe with elimusertib and prexasertib [ 23 , 35 , 37 , 38 , 39 ]. Indeed, the rate of G3/4 events was 54% with the ATR inhibitor and reached 93% with the CHK1 inhibitor.…”

“…Thrombocytopenia was less frequent in phase III randomized trials of other PARP inhibitors, with a G ≥ 3 rate below 10% ( Table 1 ). Decreased platelet counts were also observed in early phase studies of elimusertib [ 35 ], prexasertib [ 23 , 37 , 38 , 39 ] and adavosertib, where it was mainly G1-2 [ 40 , 41 , 42 , 52 ]. In case of thrombocytopenia, treatment should be withheld for values <100,000 with niraparib and <50,000 with olaparib, rucaparib and talazoparib, and then restarted at the same or at a lower dose level after count normalization [ 25 , 26 ].…”

“…Consistently, grade (G) ≥ 3 anemia according to Common Terminology Criteria for Adverse Events (CTCAE), which presented in about 20% of subjects, was less frequent with veliparib (7% in the VELIA trial) and more common with niraparib (31% and 25% in the PRIMA and NOVA trial, respectively) [ 14 , 33 , 34 ]. Decrease of hemoglobin level was also common in early phase trials evaluating the ATR inhibitors elimusertib and bezosertib [ 35 , 36 ], CHK1 inhibitor prexasertib [ 23 , 37 , 38 , 39 ] and WEE1 inhibitor adavosertib [ 40 , 41 , 42 ]. However—with the exception of elimusertib, which determined an 81% rate of G3/4 anemia—this AE was mainly low grade [ 23 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

“…Decrease of hemoglobin level was also common in early phase trials evaluating the ATR inhibitors elimusertib and bezosertib [ 35 , 36 ], CHK1 inhibitor prexasertib [ 23 , 37 , 38 , 39 ] and WEE1 inhibitor adavosertib [ 40 , 41 , 42 ]. However—with the exception of elimusertib, which determined an 81% rate of G3/4 anemia—this AE was mainly low grade [ 23 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Anemia should be managed with dose interruption according to the hemoglobin levels.…”

Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer

“…There are numerous clinical studies using adavosertib as monotherapy and in combination with chemotherapy, with encouraging results revealing that these treatment regimens are generally tolerated [ 21 , 22 , 44 , 45 , 46 ]. Our study provides preclinical data that warrant clinical trials to examine adavosertib for DTC therapy.…”