A phase II study of the cell cycle checkpoint kinases 1 and 2 inhibitor (LY2606368; Prexasertib monomesylate monohydrate) in sporadic high-grade serous ovarian cancer (HGSOC) and germline BRCA mutation-associated ovarian cancer (gBRCAm+ OvCa)

Date

07 Oct 2016

Session

Gynaecological cancers

Presenters

Jung-Min Lee

Citation

Annals of Oncology (2016) 27 (6): 296-312. 10.1093/annonc/mdw374

Authors

J. Lee1, F.H. Karzai2, A. Zimmer1, C.M. Annunziata1, S. Lipkowitz1, B. Parker1, N. Houston1, I. Ekwede1, E.C. Kohn1

Author affiliations

  • 1 Women's Malignancies Branch, National Cancer Institute, 20892 - Rockville/US
  • 2 Division Of Intramural Research, National Institute on Minority Health and Health Disparities, Rockville/US
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Background

Checkpoint kinases 1 and 2 (CHK1/2) are the primary cell cycle regulators in tumors with p53 dysfunction, such as HGSOC. The second-generation CHK1/2 inhibitor, LY2606368 showed preliminary activity in advanced cancer pts in phase 1 studies. We hypothesize that LY2606368 will result in clinical benefit in subsets of pts with HGSOC.

Methods

Eligible pts had recurrent HGSOC with negative BRCA testing or negative family history of hereditary breast and ovarian cancer syndrome (cohort 1) or a documented deleterious germline BRCA1/2 mutation (cohort 2); good end organ function and safely biopsiable disease; ECOG PS 0-2. Pts received LY2606368 monotherapy at 105 mg/m2 IV every 14 days per 28day cycle. Response was assessed every 2 cycles by RECISTv1.1, and safety by CTCAEv4.0 per cycle. The primary endpoint is overall response rate (ORR). Simon's two- stage design was used to rule out 5% ORR in favor of an ORR of 25% (alpha = 0.10; beta = 0.10). If ≥1 response is seen in the first 9 pts, then accrual continues to 24 pts per cohort. If ≥3 responses are seen in 24 pts (12.5%), this would be sufficient to warrant further study.

Results

22 women (15 HGSOC/ 7 gBRCAm+OvCa) have been treated (median age 61 [36-83]). The median number of prior therapies was 5 (1-13) for cohort 1 and 7 (3-12) for cohort 2. 5 PR (median duration of response; 9 mo [3+-9+]) have been seen in 13 evaluable cohort 1 pts (ORR 38%), two with platinum-sensitive and three with platinum-resistant disease. Four of 6 evaluable cohort 2 pts attained SD ≥4 mo (median 4.5 mo), with 0/6 responses. Grade 3 or 4 treatment-emergent AEs include neutropenia (91%; 20/22), thrombocytopenia (27%; 6/22), febrile neutropenia (9%; 2/22) and diarrhea (9%; 2/22). Grade 3 or 4 neutropenia on day 8 resolved within 7 days in 13/22 pts. 13 pts received growth factor support due to febrile neutropenia or to avoid treatment delays.

Conclusions

LY2606368 alone shows promising preliminary activity in BRCA wild type HGSOC pts and continues to enroll. Prophylactic use of G-CSF should be considered. Paired tumor biopsies and blood samples are being collected to examine potential biomarkers of response.

Clinical trial identification

NCT02203513

Legal entity responsible for the study

National Cancer Institute, NIH, Rockville, MD, USA

Funding

This work was funded by the Intramural Program of the Center for Cancer Research, NCI, National Institutes of Health, USA.

Disclosure

All authors have declared no conflicts of interest.

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