Oncotarget

Research Papers:

Phase I/Ib study of olaparib and carboplatin in heavily pretreated recurrent high-grade serous ovarian cancer at low genetic risk

Erika J. Lampert, John L. Hays, Elise C. Kohn, Christina M. Annunziata, Lori Minasian, Minshu Yu, Nicolas Gordon, Tristan M. Sissung, Victoria L. Chiou, William D. Figg, Nicole Houston and Jung-Min Lee _

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Oncotarget. 2019; 10:2855-2868. https://doi.org/10.18632/oncotarget.26869

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Abstract

Erika J. Lampert1, John L. Hays2, Elise C. Kohn1, Christina M. Annunziata1, Lori Minasian1, Minshu Yu1, Nicolas Gordon1, Tristan M. Sissung3, Victoria L. Chiou1, William D. Figg3, Nicole Houston1 and Jung-Min Lee1

1 Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

2 Ohio State University, Columbus, OH, USA

3 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Correspondence to:

Jung-Min Lee,email: leej6@mail.nih.gov

Keywords: high-grade serous ovarian cancer; BRCA wild type; olaparib; carboplatin

Received: February 26, 2019     Accepted: April 04, 2019     Published: April 23, 2019

ABSTRACT

Purpose: To investigate maximum tolerated dose (MTD), activity and predictive biomarkers of olaparib with carboplatin in BRCA wild-type (BRCAwt) high grade serous ovarian carcinoma (HGSOC) patients.

Methods: A 3+3 dose escalation study examined olaparib capsules (400 mg twice daily [BID], days 1–7) with carboplatin (AUC3-5 on day 1) every 21 days for 8 cycles, followed by olaparib 400 mg BID maintenance. Blood and tumor biopsy samples were collected pre- and on-treatment in the expansion cohort for PAR levels and proteomic endpoints.

Results: 30 patients (median 7 prior regimens [2–12], 63% (19/30) platinum-resistant) were enrolled. Dose-limiting toxicity was thrombocytopenia/neutropenia, and infection with carboplatin AUC5 (2/6 patients). MTD was olaparib 400 mg BID + carboplatin AUC4. Grade 3/4 adverse events (>10%) included neutropenia (23%), thrombocytopenia (20%), and anemia (13%). Five of 25 (20%) evaluable patients had partial response (PR; median 4.5 months [3.3–9.5]). Clinical benefit rate (PR + stable disease ≥4 months) was 64% (16/25). A greater decrease in tissue PAR levels was seen in the clinical benefit group versus no benefit (median normalized linear change −1.84 [−3.39– −0.28] vs 0.51 [−0.27– 1.29], p = 0.001) and a DNA repair score by proteomics did not correlate with response.

Conclusions: The olaparib and carboplatin combination is tolerable and has clinical benefit in subsets of heavily pretreated BRCAwt HGSOC, independent of platinum sensitivity.


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