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ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter Study Assessing the Efficacy and Safety of Adavosertib
Joyce F Liu1, Nicoletta Colombo2,3, Amit M Oza4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Purpose:
This phase IIb, single-arm, multicenter, global study (ADAGIO; ClinicalTrials.gov identifier: NCT04590248) assessed the efficacy and safety of adavosertib in patients with recurrent/persistent uterine serous carcinoma (USC) who had previously received platinum-based chemotherapy.
Methods:
Eligible patients were age 18 years and older and had histologically confirmed recurrent/persistent USC, previously treated with at least one platinum-based chemotherapy regimen, and with evidence of measurable disease. Adavosertib was administered orally at 300 mg once daily on days 1-5 and 8-12 of a 21-day cycle until discontinuation criteria were met. The primary end point was objective response rate (ORR) by blinded independent central review (BICR). Secondary end points included duration of response (DoR), progression-free survival (PFS), safety, and tolerability. Biomarkers previously associated with adavosertib response in other settings were assessed in archival tissue samples.
Results:
In 104 evaluable patients, one complete response and 26 partial responses were observed, for an ORR by BICR of 26.0% (95% CI, 17.9 to 35.5). Median DoR was 4.7 months (95% CI, 3.8 to 8.3); median PFS was 2.8 months (95% CI, 2.6 to 3.9). Biomarker analysis identified no single predictive alteration for adavosertib response, although a trend was observed for CCNE1 amplification or high cyclin E1 protein expression. Most patients (97.2%) experienced treatment-related adverse events (TRAEs), most frequently diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). Grade ≥3 TRAEs occurred in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) most common. 17.4% of patients discontinued adavosertib due to AEs (treatment-related in 14.7%).
Conclusion:
Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this population. Exploratory biomarker studies suggest CCNE1/cyclin E1 expression may enrich for response to Wee1 inhibition in USC.
Insights
Adavosertib demonstrated antitumor activity in recurrent uterine serous carcinoma but had poor tolerability. Further research into CCNE1/cyclin E1 expression may help identify patients who benefit from Wee1 inhibition.
Area of Science:
- Oncology
- Gynecologic Oncology
- Pharmacology
Background:
- Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer.
- Recurrent or persistent USC after platinum-based chemotherapy has limited treatment options.
- Adavosertib, a Wee1 inhibitor, has shown promise in preclinical and early clinical studies.
Purpose of the Study:
- To assess the efficacy and safety of adavosertib in patients with recurrent/persistent USC.
- To evaluate objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS).
- To explore potential biomarkers predictive of adavosertib response.
Main Methods:
- Phase IIb, single-arm, multicenter, global study (ADAGIO).
- 104 patients with recurrent/persistent USC received adavosertib 300 mg orally once daily.
- Primary endpoint: ORR by blinded independent central review (BICR). Secondary endpoints: DoR, PFS, safety, tolerability, and biomarker analysis.
Main Results:
- ORR by BICR was 26.0% (95% CI, 17.9 to 35.5).
- Median DoR was 4.7 months; median PFS was 2.8 months.
- Most patients (97.2%) experienced treatment-related adverse events (TRAEs), with diarrhea, nausea, and anemia being most common. Grade ≥3 TRAEs occurred in 60.6% of patients.
Conclusions:
- Adavosertib exhibited antitumor activity in recurrent/persistent USC.
- The 300 mg once daily dose was not well tolerated in this patient population.
- Exploratory biomarker studies suggest CCNE1 amplification or high cyclin E1 protein expression may predict response to Wee1 inhibition in USC.
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