Effective treatments for hormone-receptor-positive (HR+) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR+ advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38–0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31–0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, patients with recurrence during or within 12 months of completion of adjuvant therapy, and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials. The addition of everolimus to exemestane markedly prolonged PFS in patients with HR+ advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.

https://link.springer.com/content/pdf/10.1007%2Fs12325-013-0060-1.pdf

Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis

Introduction: Naphthalimides are important aromatic heterocycles with immense pharmacological significance as they serve as core scaffold for many antitumor, anti-inflammatory, antidepressant, antiprotozoal and antiviral agents, etc. The tricyclic planar ring system of naphthalimide is primarily responsible for its intercalation with DNA to perturb the cellular events and the substitution pattern of the molecule leads to several other applications. The promising pharmacological activity profile and ease of synthesis have been attractive in design and development of new class of naphthalimides and their conjugates as various potential therapeutic agents. Few of such molecules are currently under preclinical and clinical evaluations. Areas covered: Important patents focusing on naphthalimides as potential class of therapeutics, published between the period of 2006 – 2011have been covered. The reports are presented together with a review of the related structural chemical space. This review mainly focuses on...

Naphthalimide derivatives with therapeutic characteristics: a patent review

Co-targeting estrogen receptor and HER2 pathways in breast cancer.

First-line endocrine therapy by estrogen antagonism or suppression of estrogen achieves objective responses (ORs) and clinical benefit (CB) in around 30% and 50% of estrogen receptor-positive metastatic breast cancer patients, respectively. Aromatase inhibitors (Als) are the most effective treatment in previously untreated postmenopausal women. Tamoxifen is an effective alternative. The optimal endocrine therapy on relapse remains uncertain. Tamoxifen and fulvestrant achieve CB in around 50% of patients and ORs of 10%. CB of exemestane after nonsteroidal Als is 30% to 50% but ORs are rare. Targeted agents (eg, everolimus) plus endocrine therapy are likely to become increasingly important in overcoming endocrine resistance.

https://www.hemonc.theclinics.com/article/S0889-8588(13)00056-7/pdf

Endocrine Therapy for Advanced/Metastatic Breast Cancer

This invention pertains to pharmaceutical compositions comprising certain carbamic acid compounds (e.g., which inhibit HDAC (histone deacetylase) activity) (e.g., PXD-101, N hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide)) and one or more additional ingredients selected from cyclodextrin, arginine, and meglumine. The present invention also pertains to the use of such compositions, for example, in the inhibition of HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.

Pharmaceutical Formulations Of Hdac Inhibitors

The present embodiments relate to compositions and methods of treatment of cancer. More particularly, the present embodiments relate to the combination of an ERα+ ligand with an HDACi for the treatment of cancer, methods of treating cancer and pharmaceutical compositions for treating cancer.

COMBINATION OF ERa+ LIGANDS AND HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF CANCER

128 Background: Histone deacetylase inhibitors (HDACi) prevent the emergence of drug tolerant clones and sensitize cells to a variety of anti-cancer therapies. We previously reported ENCORE 301, a randomized placebo controlled phase II study comparing exemestane with (EE) and without (EP) the HDACi entinostat met its primary endpoint of prolonging progression free survival (PFS) (4.3 months vs 2.3 months) and extending overall survival (OS) benefit (26.9 vs 19.8 months). In order to characterize and better understand the OS benefit, exploratory analyses were conducted. Methods: Hazard ratios (HR) for treatment were estimated from the Cox proportional hazards model, with EP serving as the reference treatment in the calculations. Inferential comparisons between treatment groups were made using the log-rank test. Results: Analysis of OS across multiple subsets of interest demonstrated a consistent benefit in EE group versus EP. Sensitivity analysis of baseline characteristics potentially impacting OS did not...

Characterization of the overall survival benefit in ENCORE 301, a randomized, placebo-controlled phase II study of exemestane with and without entinostat in ER+ postmenopausal women with metastatic breast cancer.

591 Background: Entinostat (ENT) is an oral, class 1 isoform selective histone deacetylase inhibitor shown to extend progression free and overall survival when combined with exemestane (EXE) in post-menopausal women with estrogen receptor positive (ER+) metastatic breast cancer (MBC) who have progressed on prior non-steroidal aromatase inhibitors (Yardley et al; JCO 31:2128;2013). Based on these results ENT was granted Breakthrough Therapy designation by the FDA for this indication. This Phase 1 study evaluated the effect of food on ENT PK in patients (pts) with MBC and advanced non-small cell lung cancer (NSCLC). Methods: A total of 17 pts (14 postmenopausal ER+ MBC and 3 NSCLC) were randomized 1:1 to receive ENT 10 mg administered Day 1 and 15 of a 28 day lead-in cycle, fasting and with food. Pts randomized to ENT with food on Cycle 1 Day 1 (C1D1) received ENT fasted on Cycle 1 Day 15 (C1D15); pts randomized to ENT fasted on C1D1 received ENT with food on C1D15. Blood samples were obtained pre-dose C1D1...

A phase 1 study to assess the food effect on the pharmacokinetics (PK) of entinostat.

Kombination von er+-liganden und histondeacetylase-hemmern zur behandlung von krebs

MammaPrint® 10-Year Follow Up Results from a German Breast Cancer Cohort Study

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