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Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and
Erika P Hamilton1, Gerald S Falchook2, Judy S Wang3,4
1Sarah Cannon Research Institute, 250 25th Avenue North, Nashville, TN, 37203, USA. Erika.Hamilton@scri.com.
Background:
Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors.
Objective:
The safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).
Patients And Methods:
Eligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle.
Results:
A total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort.
Conclusions:
Adverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy.
Trial Registration:
ClinicalTrials.gov, NCT02511795 (registration: 28 July 2015).
Insights
This study evaluated adavosertib plus olaparib in patients with refractory solid tumors. The combination showed manageable safety but limited antitumor activity, defining recommended doses for further trials.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Adavosertib is a selective Wee1 inhibitor; olaparib is a PARP inhibitor.
- Preclinical studies suggest adavosertib can enhance the efficacy of PARP inhibitors.
- This study investigated the combination of adavosertib and olaparib in solid tumors.
Purpose of the Study:
- To evaluate the safety, tolerability, and efficacy of adavosertib plus olaparib.
- To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination therapy.
- To assess the combination in patients with refractory solid tumors, including small-cell lung cancer (SCLC).
Main Methods:
- A phase I/II clinical trial was conducted with dose-finding (Part A) and dose-expansion (Part B) cohorts.
- Patients received adavosertib (once or twice daily) with olaparib (twice daily) on defined schedules.
- Eligibility criteria included refractory solid tumors or platinum-sensitive/relapsed SCLC.
Main Results:
- The MTD and RP2D were established for both twice-daily and once-daily adavosertib dosing schedules in combination with olaparib.
- Common treatment-related adverse events included fatigue, diarrhea, decreased appetite, nausea, and anemia.
- In Part A, the overall objective response rate (ORR) was 14.8%. In the SCLC cohort, ORR was 11.1% with a disease control rate of 22.2%.
Conclusions:
- Adverse events and dose-limiting toxicities were manageable and consistent with the known safety profiles of adavosertib and olaparib.
- The combination therapy demonstrated limited overall antitumor activity.
- The MTD and RP2D were successfully defined, providing a basis for future clinical investigations.
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