Phase II Pharmacological Study With Wee-1 Inhibitor MK-1775 Combined With Carboplatin in Patients With p53 Mutated Epithelial Ovarian Cancer and Early Relapse (< 3 Months) or Progression During Standard First Line Treatment

TP53-mutated ovarian cancer refractory or resistant to first-line carboplatin plus paclitaxel

Cohort I: 23; 14 Pt-R (within 3 months after last Pt-regimen), 9 Pt-Rf; Cohort II: 32 primary Pt-R

Recurrence

Open-Label, Non-randomized

ORR, DoR, PFS, OS, evaluated per RECIST

TP53 MUT

ORR: 43% (1CR, 8PR, n=21)
DCR: 76.2% (1CR, 8PR, 7SD, n=21)
PFS: 5.3 months (2.3-9.0)
OS: 12.6 months (4.9-19.7)

Cohort II: 32 primary Pt-R patients; 26 with 1 prior therapy, 6 with 2 prior therapy (2nd line non-platinum regimen)
225 mg adavosertib for 2.5 days with CarboPt AUC 5 in 21 day cycles
ORR: 41% (12PR, n=29)
DCR: 93.1% (12PR, 15SD, n=29)
DoR: 6.2 months
PFS: 5.6 months

Exploratory analysis Pt status:
Pt-R (n=13): ORR: 62% (1CR, 7PR); DCR: 84.6% (1CR, 7PR, 3SD)
Pt-Rf (n=8): ORR: 13% (1PR); DCR: 62.5% (1PR, 4SD)

Serious AE: none
Grade 3-4 AE: thrombocytopenia (48%), neutropenia (39%), anemia (9%)

Promising activity in TP53-mutated primary Pt-R and Pt-Rf patients

Leijen S et al. Phase II Study of WEE1 Inhibitor AZD1775 Plus Carboplatin in Patients With TP53-Mutated Ovarian Cancer Refractory or Resistant to First-Line Therapy Within 3 Months. J Clin Oncol (2016) 34(36):4354-4361
https://www.ncbi.nlm.nih.gov/pubmed/27998224

Embaby A et al. WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study. Gynecol Oncol (2023) 174:239-246
https://pubmed.ncbi.nlm.nih.gov/37236033/