Abstract CT025: Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation
Authors: Hamilton Erika , Falchook Gerald S. , Wang Judy S. , Fu Siqing , Oza Amit , Karen So , Imedio Esteban Rodrigo , Kumar Sanjeev , Ottesen Lone , Mugundu Ganesh M. , Chmielecki Juliann , Jones Suzanne , Spigel David R. , Li Bob T. 
Published: August 2019

Background: Preclinical data suggest that adavosertib (AZD1775), a highly selective Wee1 inhibitor, enhances the antitumor effect of PARP inhibitors such as olaparib. The dose-escalation part of this Phase Ib study (NCT02511795) investigated the safety and tolerability of adavosertib plus olaparib in patients (pts) with refractory solid tumors to determine a maximum tolerated dose (MTD) and recommended Phase II dose (RP2D).

Methods: Pts received adavosertib (QD or 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 (Table).

The MTD was the highest dose at which &lt;1/3 of evaluable pts had a dose-limiting toxicity (DLT). DLTs were hematologic grade (gr) ≥4 AEs lasting &gt;7 days, gr 3 thrombocytopenia with gr ≥2 bleeding, non-hematologic gr ≥3 AEs (excluding nausea, vomiting or diarrhea that responds to supportive care), liver function gr ≥3 AEs lasting &gt;48 hours or changes consistent with Hy’s Law, or any other toxicity that disrupted dosing for &gt;7 days.

Results: 119 pts were treated (84 female; median age 59; most common primary tumor sites: ovary [21%], breast [16%], lung [12.6%]) (Table). The most common gr ≥3 AEs were anemia (n=28, 23.5%), neutropenia (n=26, 21.8%), and thrombocytopenia (n=20, 16.8%) (all grouped terms). The most common DLTs were thrombocytopenia (n=4) and neutropenia (n=4); two pts experienced both. There were 4 SAEs with an outcome of death, 1 was treatment related. ORR for the total population, cohort 4.2 and cohort 7.4 was 11.1%, 30.8% and 0%, respectively. DCR was 55.7%, 76.9% and 53.8%, respectively. PK and biomarker data will be presented.

Conclusions: Treatment with adavosertib plus olaparib showed antitumor activity, mostly at the MTD/RP2D for the BID schedule, which was determined to be adavosertib 175 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID. The RP2D for QD schedule was adavosertib 200 mg (3/4) for 2/3 weeks plus olaparib 200 mg BID.

Summary of study cohortsCohortAdavosertib doseOlaparib doseAdavosertib schedule, daysOlaparib schedule, daysPatients, n (evaluable,* n)Patients with a DLT, n (%)Grade ≥3 AEs,† n (%)ORR, n (%)DCR, n (%)1125 mg BID (3/4)100 mg BID1–3/8–101–143 (2)01 (33.3)03 (100)2150 mg BID (3/4)100 mg BID1–3/8–101–144 (4)02 (50)1 (25)2 (50)3.1175 mg BID (3/4)100 mg BID1–3/8–101–144 (2)03 (75)03 (75)3.2150 mg BID (3/4)200 mg BID1–3/8–101–147 (5)04 (57.1)1 (14.3)5 (71.4)4.1175 mg BID (3/4)200 mg BID1–3/8–101–147 (7)04 (57.1)1 (14.3)4 (57.1)4.2175 mg BID (3/4)200 mg BID1–3/8–101–2114 (11)1 (9.1)9 (64.3)4 (30.8)10 (76.9)4.3175 mg BID (3/4)200 mg BID1–3/8–10/15–171–2114 (11)2 (18.2)13 (92.9)1 (7.7)7 (50)5175 mg BID (3/4)300 mg BID1–3/8–101–145 (5)1 (20.0)3 (60.0)2 (50)4 (100)6.1250 mg QD (5/2)200 mg BID1–5/8–121–217 (4)2 (50.0)6 (85.7)1 (20)1 (16.7)6.2200 mg QD (5/2)200 mg BID1–5/8–121–217 (5)2 (40.0)4 (57.1)01 (14.3)7.1250 mg QD (3/4)200 mg BID1–3/8–101–2116 (14)2 (14.3)12 (75)010 (62.5)7.2250 mg QD (3/4)200 mg BID1–3/8–10/15–171–214 (4)1 (25.0)3 (75)1 (25)3 (75)7.3300 mg QD (3/4)200 mg BID1–3/8–101–213 (3)1 (33.3)2 (66.7)007.4200 mg QD (3/4)200 mg BID1–3/8–101–2113 (12)1 (8.3)3 (23.1)07 (53.8)8.1200 mg QD (3/4)300 mg BID1–3/8–101–2111 (9)1 (11.1)4 (36.4)04 (40)*Evaluable patients received &gt;75% of the planned dose of adavosertib and olaparib; †Common Terminology Criteria for Adverse Events. DCR, disease control rate; ORR, objective response rate

Citation Format: Erika Hamilton, Gerald S. Falchook, Judy S. Wang, Siqing Fu, Amit Oza, So Karen, Esteban Rodrigo Imedio, Sanjeev Kumar, Lone Ottesen, Ganesh M. Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Bob T. Li. Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT025.