Showing papers by "Juliann Chmielecki published in 2019"

Genomic correlates of disease progression and treatment response in prospectively characterized gliomas

Abstract: Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial.

Abstract: 9020Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third generation EGFR-TKI, showed superior efficacy to comparator EGFR-TKIs as first line treatment for EGFR mutation-pos...

Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study.

Abstract: 5513Background: Adavosertib (AZD1775; A), a highly selective WEE1 inhibitor, demonstrated activity and tolerability in combination with carboplatin (C) in primary PROC. This study (NCT02272790) ass...

Abstract CT025: Phase Ib study of adavosertib in combination with olaparib in patients with refractory solid tumors: Dose escalation

Abstract: 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 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 >48 hours or changes consistent with Hy’s Law, or any other toxicity that disrupted dosing for >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. 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.

Abstract CT012: Open-label, multicenter, Phase Ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: Expansion cohorts

Abstract: Background Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. Previously we reported safety and efficacy of adavosertib monotherapy in patients (pts) with advanced solid tumors (NCT02482311; Bauer et al Cancer Res 2016;76[14 Suppl]); here we report safety and efficacy data from expansion cohorts based on tumor type. Methods A total of 80 pts grouped into 6 biomarker-matched cohorts (Table) received adavosertib (175 mg PO bid; days 1–3 and 8–10 per 21-day cycle). Eligible pts had: confirmed diagnosis of ovarian cancer (OC), small-cell lung cancer (SCLC) or triple-negative breast cancer (TNBC); prior treatment (Tx) for metastatic/recurrent disease (≥3 prior Tx for pts with BRCAwt OC; progression following PARPi Tx for BRCA1/2m OC pts; ≤1 chemotherapy-based Tx for SCLC and ≥1 chemotherapy-based Tx for TNBC); measurable disease. Primary objective assessments: ORR; DCR; PFS (RECIST v1.1); safety. Tumor assessments were performed every 6 weeks in year 1 and every 12 weeks thereafter until disease progression or intolerable toxicity. Blood and tumor samples were collected for correlative biomarker and pharmacokinetic (PK) analyses. Results Median total Tx duration was 2.4 months. Most frequently reported adverse events (AEs) were diarrhea (61%), nausea (50%) and fatigue (43%). Most commonly reported grade ≥3 AEs were diarrhea (7.5%), nausea, fatigue and small intestine obstruction (6%). AEs leading to dose interruptions (22.5%), reductions (11.3%) or discontinuations (16.3%) were reported. The study showed preliminary antitumor activity, particularly in BRCAwt as well as PARPi-failure BRCAm OC pts (Table). PK and biomarker analyses will be presented. Conclusions Adavosertib was generally well tolerated and showed preliminary antitumor activity. DCR was modest across all patient cohorts. Citation Format: Todd M. Bauer, Kathleen Moore, Janet S. Rader, Fiona Simpkins, Alain Mita, J Thaddeus Beck, Lowell Hart, Quincy Chu, Amit Oza, Anna V. Tinker, Karen So, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Suzanne Jenkins, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Siqing Fu. Open-label, multicenter, Phase Ib study to assess safety, tolerability and efficacy of adavosertib monotherapy in patients with advanced solid tumors: Expansion cohorts [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 CT012.

Abstract CT022: A Phase Ib study of Wee1 inhibitor adavosertib in patients with advanced solid tumors

Abstract: Background: Adavosertib is a highly selective inhibitor of Wee1, a crucial regulator of intra-S and G2/M cell cycle checkpoints. This Phase Ib study (NCT02610075) investigated dosing and schedule for adavosertib monotherapy and determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Pts received adavosertib orally once (QD) or twice daily (BID) on a 5/9 schedule (5 days on treatment followed by 9 days off) in 14-day cycles, or one of two 5/2 dosing schedules (5 days on followed by 2 days off; weekly or 2 out of 3 weeks) in 21-day cycles. MTD was determined using a 3+3 dose-escalation cohort design. DLTs were defined as toxicities related to adavosertib, occurring during the first cycle. PK and biomarker analyses were performed on blood samples. Pts’ response to treatment was assessed using RECIST v1.1. Results: 62 pts (female, 64.5%; median age, 61.5 years; most common primary tumor sites: lung [24.2%] and ovary [21.0%]) received treatment (QD schedule, n=50; BID schedule, n=12) (Table 1). Median treatment duration was 1.77 months. Adavosertib was steadily absorbed (median time to max concentration: 2.0-4.15 h) and slowly eliminated (mean half-life: 5-12 h). AEs leading to dose reductions, interruptions and discontinuations were reported by 17 (27.4%), 25 (40.3%) and 4 (6.5%) pts, respectively. The most common grade ≥3 AEs were anemia, neutropenia (both n=9, 14.5%) and diarrhea (n=8, 12.9%). The overall response rate was 3.4% (n=2 [thymoma; anal]), disease control rate 48.4% (n=30) and median progression-free survival 2.7 months. Circulating-tumor-derived DNA pharmacodynamic analyses will be presented. Conclusions: The MTD was determined to be 125 mg (BID 5/9) and 300 mg (QD 5/2 and 5/9) for 2/3 weeks, with 300 mg (QD 5/2) being the RP2D. The safety/tolerability profile was considered acceptable. Adavosertib monotherapy showed preliminary evidence of antitumor activity in a heavily pretreated patient population. Citation Format: Gerald S. Falchook, Jasgit Sachdev, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh Mugundu, Juliann Chmielecki, Suzanne Jones, David R. Spigel, Melissa Johnson. A Phase Ib study of Wee1 inhibitor adavosertib in patients with advanced solid tumors [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 CT022.