Abstract P2-16-19: Fulvestrant with or without selumetinib (Sel, AZD6244), a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI): A multicenter randomized placebo-controlled double-blind phase II trial, SAKK21/08

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

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Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: A multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08

European Journal of Cancer ◽

10.1016/j.ejca.2015.03.016 ◽

2015 ◽

Vol 51 (10) ◽

pp. 1212-1220 ◽

Cited By ~ 22

Author(s):

Khalil Zaman ◽

Ralph Winterhalder ◽

Christoph Mamot ◽

Ursula Hasler-Strub ◽

Christoph Rochlitz ◽

...

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitor ◽

Phase Ii ◽

Phase Ii Trial ◽

Inhibitor Therapy ◽

Double Blind ◽

Aromatase Inhibitor Therapy

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Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1005 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1005-1005 ◽

Cited By ~ 13

Author(s):

Robert Hugh Jones ◽

Margherita Carucci ◽

Angela Claire Casbard ◽

Rachel Butler ◽

Fouad Alchami ◽

...

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitor ◽

Disease Progression ◽

Phase Ii ◽

Phase Ii Trial ◽

Akt Pathway ◽

Double Blind ◽

Double Blind Placebo ◽

Er Positive ◽

Positive Breast Cancer

1005 Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.

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Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway

BioMed Research International ◽

10.1155/2015/414250 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 21

Author(s):

Xiang-Yan Chen ◽

Jie Zhou ◽

Li-Ping Luo ◽

Bin Han ◽

Fei Li ◽

...

Keyword(s):

Breast Cancer ◽

Protein Kinase ◽

Mrna Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Black Rice ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

Overexpression of human epidermal growth factor receptor 2 (HER2) drives the biology of 30% of breast cancer cases. As a transducer of HER2 signaling, RAS/RAF/MAPK pathway plays a pivotal role in the development of breast cancer. In this study, we examined the molecular mechanisms underlying the chemopreventive effects of black rice anthocyanins (BRACs) extract and identified their molecular targets in HER2+breast cancer cells. Treatment of MDA-MB-453 cells (HER2+) with BRACs inhibited cell migration and invasion, suppressed the activation of mitogen-activated protein kinase kinase kinase (RAF), mitogen-activated protein kinase kinase (MEK), and c-Jun N-terminal kinase (JNK), and downregulated the secretion of matrix metalloproteinase 2 (MMP2) and MMP9. BRACs also weakened the interactions of HER2 with RAF, MEK, and JNK proteins, respectively, and decreased the mRNA expression ofraf,mek, andjnk. Further, we found combined treatment with BRACs and RAF, MEK, or JNK inhibitors could enhance the antimetastatic activity, compared with that of each treatment. Transient transfection with small interfering RNAs (siRNAs) specific forraf,mek, andjnkinhibited their mRNA expression in MDA-MB-453 cells. Moreover, cotreatment with BRACs and siRNA induces a more remarkable inhibitory effect than that by either substance alone. In summary, our study suggested that BRACs suppress metastasis in breast cancer cells by targeting the RAS/RAF/MAPK pathway.

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