The phase IIIb international study C-1 (NCT02941926) aims to assess the safety and efficacy of RIBO + LET in men and women who have not received prior ET for HR+, HER2– ABC. Overall more than 3000 ...pts were enrolled. Here we present interim efficacy and safety results from the Italian cohort.
Pts with HR+, HER2– ABC, ≤1line of prior chemotherapy, and no prior ET for ABC received RIBO (600mg/day, 3 wk on/1 wk off) + LET (2.5mg/day). Men and premenopausal women received concomitant goserelin. The primary endpoint was safety and tolerability. Secondary endpoints included time to progression (TTP), overall response rate (ORR) and clinical benefit rate (CBR).
From April 2017, to December 2017, 554 pts were enrolled in the C-1 trial in Italy. Median age was 58 years (range 20–87); 1,1% (6) of pts were male, 29,1% were premenopausal women and 69.3% post-menopausal. 2,3%(13) of pts presented CNS metastases and 4,5% (25) skin involvement at study entry. At the cut-off date for this Analysis (August 8, 2018) 66,1% of the pts were still on treatment, 29,8% discontinued, mainly for progression (18,4%) or AEs (10,3 %). The most common all-grade any-cause AEs were neutropenia (69,7%), nausea (29,6%), and leukopenia (28,7%). Grade 3 or 4 elevations in ALT and AST levels were reported in 6,4% and 4,3%, respectively. Prolongation of the QTcF interval to more than 480 msec occurred in 3.1% of patients. 30,3% of patients required a dose reduction (24% one dose, 24,9% due to AEs). ORR was 20,4% (95% CI, 17,1%-24%) and CBR was 69,7% (95% CI, 65,7%-73,5%). TTP was not reached.
This interim analysis confirm the predictable and manageable safety profile of RIBO in combination with LET as first-line treatment for HR+, HER2– ABC. The Italian C-1 cohort is the largest hormono-sensitive Italian population ever published with a CDK 4/6 inhibitor, including 6 male patients and 13 patients with CNS metastases that could give valuable information on this patient’s subgroups that still represent an unmet need.
EudraCT: 2016-003467-19, release date 2016-12-08 Protocol n. CLEE011A2404 NCT02941926.
Novartis Pharma AG.
Novartis Pharma AG.
M. De Laurentiis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. M. Mazza: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): istituto gentili; Honoraria (self): Celgene; Honoraria (self): astrazeneca. M. Mansutti: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Celgene. R. Masetti: Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: medtronic. Z. Ballatore: Honoraria (self), writing engagement and public speaking: Ipsen. R. Torrisi: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD. A. Michelotti: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: astrazeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: teva; Advisory / Consultancy: Pfizer. A. Zambelli: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: astrazeneca. D. Generali: Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Pfizer; Honoraria (self): Roche. P. Vici: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. A. Fabi: Honoraria (self), Speaker Bureau / Expert testimony: Roche; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony: astrazeneca; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer. P. Marchetti: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: bms; Honoraria (self), Advisory / Consultancy: astrazeneca; Honoraria (self), Advisory / Consultancy: incyte; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: molteni; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD. S. Spazzapan: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: gentili; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), principal investigator of trials: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Takeda; Honoraria (self), Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, principal investigator of trials: Roche; Honoraria (self), Travel / Accommodation / Expenses: tesaro; Honoraria (self), Speaker Bureau / Expert testimony: astrazeneca; Research grant / Funding (institution), principal investigator of trials: abbvie. A. Frassoldati: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, plus writing engagement: astrazeneca; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer. G. Sarobba: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: teva. D. Grasso: Full / Part-time employment: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: astrazeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Travel / Accommodation / Expenses: pierrefabre. C. Zamagni: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: teva; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: istituto gentili; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: eliLilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: tesaro. All other authors have declared no conflicts of interest.
The clinical use of doxorubicin, a highly active anticancer drug, is limited by its severe cardiotoxic side effects. Increased oxidative stress and apoptosis have been implicated in the ...cardiotoxicity of doxorubicin. Carvedilol is an adrenergic blocking agent with potent anti-oxidant activity. In this study we investigated whether carvedilol has protective effects against doxorubicin-induced free radical production and apoptosis in cultured cardiac muscle cells, and we compared the effects of carvedilol to atenolol, a β-blocker with no anti-oxidant activity. Reactive oxygen species (ROS) generation in cultured cardiac muscle cells (H9c2 cells) was evaluated by flow cytometry using dichlorofluorescein (DCF) and hydroethidine (HE). Apoptosis was assessed by measuring annexin V–FITC/propidium iodide double staining, DNA laddering, levels of expression of the pro-apoptotic protein Bax-α and the anti-apoptotic protein Bcl-2, and caspase-3 activity. Pre-treatment with carvedilol significantly attenuated the doxorubicin-induced increases in DCF (
P < 0.001 compared to cells not pre-treated with carvedilol) and HE (
P < 0.01) fluorescence. Doxorubicin increased the fraction of annexin V–FITC-positive fluorescent cells, while pre-treatment with carvedilol reduced the number of positive fluorescent cells (
P < 0.01). Doxorubicin-induced DNA fragmentation to a clear ladder pattern, while carvedilol prevented DNA fragmentation. Doxorubicin-induced a fall in mRNA expression of the anti-apoptotic Bcl-2 and an increase in the expression of the pro-apoptotic Bax-α. Carvedilol pre-treatment blunted both the decrease of Bcl-2 (
P < 0.01) and the increase of Bax-α mRNA expression (
P < 0.01). Caspase-3 activity significantly increased after the addition of doxorubicin. Concurrently, carvedilol partially inhibited the doxorubicin-induced activation of caspase-3 (
P < 0.01). Atenolol did not produce any effect in preventing doxorubicin-induced ROS generation and cardiac apoptosis. Our results suggest that carvedilol is potentially protective against doxorubicin cardiotoxicity by decreasing free radical release and apoptosis in cardiomyocytes.
Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. ...Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.
The current treatment of chronic myelogenous leukemia (CML) is one of the most successful examples of molecularly targeted therapy in cancer. The identification of the fusion oncogene BCR-ABL allowed ...the discovery of small molecule inhibitors of its tyrosine kinase activity which, in turn, have literally revolutionized the treatment of this disease. However, large part of a successful clinical management of CML relies on appropriate diagnosis, molecular monitoring and identification of mutations potentially leading to drug resistance. These issues are discussed here together with an overview on how patients treated with tyrosine kinase inhibitors should be monitored.
PDF
