In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT013-CT013
Abstract:
Many cancers are associated with DNA repair and cell cycle mutations that result in G1/S checkpoint deficiencies and higher levels of endogenous damage and replication stress. This can lead to dependency on WEE1 kinase, which provides an important G2/M checkpoint, allowing repair of DNA damage prior to cells entering mitosis. AZD1775 is a highly selective, small-molecule inhibitor of WEE1. A prior monotherapy study of oral AZD1775 in patients (pts) with refractory solid tumors established a maximum tolerated dose of 225 mg PO BID X 5 doses on weeks (wks) 1 and 2 every 3-wks and activity in pts with BRCA1/2 mutations (Do, JCO, 2015). A subsequent open-label Phase Ib study has been undertaken to further assess the safety and tolerability of AZD1775 monotherapy. Here we report initial safety and efficacy findings from this ongoing study. Pts with advanced solid tumors who have received prior chemotherapy are eligible. The primary objective is assessment of the safety and tolerability of AZD1775 dosing (capsules) BID x 6 doses on days (D) 1-3 and 8-10 every 21 D. Pts are treated until disease progression or intolerable toxicity, with restaging every 6 wks. PK analysis and tumor genetic profiling are performed. 12 pts with the following tumor types were recruited into the safety run-in: small-cell lung (SCLC) (4), non-small-cell lung (1), head and neck (2), ovarian (2), breast (1), pancreas (1), and unknown primary (1). The median number of prior regimens was 3 (range, 1-12). 7 pts were treated at the initial dose of 200 mg BID with 3 pts having dose-limiting toxicities (DLTs) including grade (G) 2 volume depletion/G3 anemia, G3 diarrhea, and G3 nausea/vomiting and were reduced to 175 mg BID. 5 additional pts were then treated with AZD1775 175 mg BID with the addition of antiemetic prophylaxis. Treatment (tx)-related toxicities for all pts included: nausea (75% G1-4; 17% G3/4), vomiting (67% G1-4; 17% G3/4), fatigue (58% G1-4; 8% G3/4), and diarrhea (58% G1-4; 17% G3/4); 4 pts experienced DLTs. As of 1/22/2016, 7 pts remain on tx. Responses: PR (2/12, 17%); SD (2/12, 17%); PD (7/12, 58%); not evaluable (1/12, 8%). Next generation sequencing data were generated for tumors from 10 pts. The 2 PRs were observed in pts with SCLC with somatic mutations in both TP53 and RB1. One of the pts also had a somatic mutation in BRCA1 and has been on tx for 6 months following 4 prior lines of tx. The second pt has been on tx for 5 months and had received 2 prior lines of tx. Tx is ongoing for both pts. Expansion cohorts have been initiated at 175 mg BID D1-3 and 8-10 in ovarian cancer, triple-negative breast cancer, and SCLC, with the objective of further evaluating safety, tolerability, and efficacy of AZD1775 and its association with molecular markers of G1/S deregulation, DNA damage repair deficiencies, and oncogenic driver mutations. Citation Format: Todd M. Bauer, Suzanne F. Jones, Carol Greenlees, Carl Cook, Ganesh M. Mugundu, Philip J. Jewsbury, Andrew J. Pierce, Mark J. O’Connor, Melissa L. Johnson, J. Thaddeus Beck, Kathleen N. Moore, Lowell L. Hart, Jeffery R. Infante, Howard A. Burris, David Spigel. A phase Ib, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of AZD1775 monotherapy in patients with advanced solid tumors: initial findings. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT013.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-CT013
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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