Randomized phase II trial of venetoclax + fulvestrant versus fulvestrant in estrogen receptor+, HER2– locally advanced or metastatic breast cancer following recurrence or progression during or after a CDK4/6 inhibitor: VERONICA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS1108-TPS1108
Author(s):  
Geoffrey J Lindeman ◽  
Aditya Bardia ◽  
Rebecca Bowen ◽  
Aulde Flechais ◽  
Guiyuan Lei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Ecog Performance Status ◽  
Patient Reported

TPS1108 Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.

scholarly journals A Prospective, Randomized, Placebo-Controlled Study of a Combination of Simvastatin and Chemotherapy in Metastatic Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Hiba Alarfi ◽  
Lama A. Youssef ◽  
Maher Salamoon
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Controlled Trial ◽  
Performance Status ◽  
Objective Response ◽  
Metastatic Breast ◽  
High Sensitivity ◽  
Controlled Study ◽  
Ecog Performance Status ◽  
Baseline Values

Preclinical studies support the anticancer activity of statins; however, the existing clinical evidence is inconsistent and not definitive. Our study aimed at evaluating a postulated cancer chemo-sensitizing effect of statin (simvastatin) in a cohort of metastatic breast cancer (MBC) patients. We designed a prospective, single-centered, randomized, double blinded, placebo-controlled trial that encompassed MBC patients with an ECOG Performance Status Scale ≤2 and scheduled to be treated with a chemotherapy regimen consisting of carboplatin and vinorelbine every 3 weeks at Al-Baironi Hospital, Damascus, Syria. Patients were enrolled between August 2011 and July 2012 and randomly allocated to receive a 15-day course of either simvastatin (40 mg) or placebo seven days prior to the first day of each chemotherapy cycle and then continued for eight days in each individual cycle. Primary endpoints were objective response rate (ORR) and toxicity, and the secondary endpoint was overall survival (OS). Eighty-two patients met the inclusion criteria and consented. ORR (35% vs. 32.5%) and predominant toxicity and grade ≥3 neutropenia (occurred in 30% vs. 40% of the patients) were not significantly different between simvastatin and placebo groups, respectively. Over a median follow-up of 44 months (range, 10–60), median OS was 15 months in the simvastatin group and 17 the in placebo group (hazard ratio (HR) = 1.16, 95% CI (0.70–1.91), P=0.57). Elevated baseline values of high-sensitivity C-reactive protein (hsCRP >10 mg/l), lactate dehydrogenase (LDH >480 U/L), and chemotherapy being ≥2nd line were significantly associated with shorter OS for the total cohort in both Univariate and multivariate analyses. Our data prove a safe profile of simvastatin at 40 mg per day combined with carboplatin and vinorelbine in MBC patients but without any beneficial increase of tumor sensitivity to chemotherapy. Moreover, we demonstrated a strong clinical advantage of baseline values of hsCRP and LDH as useful prognostic tools in MBC patients. This trial is registered with ISRCTN12964275.

Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1002-1002 ◽  
Author(s):  
Cristina Saura ◽  
Mafalda Oliveira ◽  
Yin-Hsun Feng ◽  
Ming-Shen Dai ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Phase Iii ◽  
Open Label ◽  
Cns Disease ◽  
Patient Reported

1002 Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m2 bid po) or L (1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.

scholarly journals A Prospective, Randomized, Placebo Controlled Study of a Combination of Simvastatin and Chemotherapy in Metastatic Breast Cancer

2020 ◽  
Author(s):  
Hiba Alarfi ◽  
Lama A. Youssef ◽  
Maher Salamoon
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Controlled Trial ◽  
Performance Status ◽  
Objective Response ◽  
Metastatic Breast ◽  
High Sensitivity ◽  
Controlled Study ◽  
Ecog Performance Status ◽  
Baseline Values

Abstract Preclinical studies support anticancer activity of statins, however, the existing clinical evidence are inconsistent and not definitive. Our study aimed at evaluating a postulated cancer chemo sensitizing effect of statin (simvastatin) in a cohort of metastatic breast cancer (MBC) patients. We designed a prospective, single-centered, randomized, double blinded, and placebo controlled trial that encompassed MBC patients with an ECOG Performance Status scale ≤2 and scheduled to be treated with a chemotherapy regimen consisting of carboplatin and vinorelbine every 3 weeks at Al-Baironi Hospital, Damascus, Syria. Patients were enrolled between August 2011 and July 2012, and randomly allocated to receive a 15-day course of either simvastatin (40 mg) or placebo seven days prior to the first day of each chemotherapy cycle, and then continued for eight days in each individual cycle. Primary endpoints were objective response rate (ORR) and toxicity, and secondary endpoint was overall survival (OS).Eighty-Two patients met the inclusion criteria and consented. ORR (35% vs. 32.5%) and predominant toxicity; grade≥3 neutropenia (occurred in 30% vs. 40% of the patients) were not significantly different between simvastatin and placebo groups, respectively. Over a median follow-up of 44 months (range, 10-60), median OS was 15 months in simvastatin group and 17 in placebo group (Hazard ratio (HR)=1.16, 95% CI (0.70-1.91), P=0.57). Elevated baseline values of high-sensitivity C-reactive protein (hsCRP >10 mg/l), lactate dehydrogenase (LDH >480 U/L) and chemotherapy being ≥2nd line significantly associated with shorter OS for the total cohort in both Univariate and multivariate analyses. Our data prove a safe profile of simvastatin at 40 mg per day combined with carboplatin and vinorelbine in MBC patients, but without any beneficial increase of tumor sensitivity to chemotherapy. Moreover, we demonstrated a strong clinical advantage of baseline values of hsCRP and LDH as useful prognostic tools in MBC patients.Trial registration: ISRCTN12964275. Retrospectively registered.

scholarly journals Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

2015 ◽  
Vol 33 (6) ◽  
pp. 594-601 ◽  
Author(s):  
Peter A. Kaufman ◽  
Ahmad Awada ◽  
Chris Twelves ◽  
Louise Yelle ◽  
Edith A. Perez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Randomized Study ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Status ◽  
Open Label ◽  
Eribulin Mesylate

Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

scholarly journals A Prospective, Randomized, Placebo Controlled Study of a Combination of Simvastatin and Chemotherapy in Metastatic Breast Cancer

2019 ◽  
Author(s):  
Hiba Alarfi ◽  
Lama Youssef ◽  
Maher Salamoon
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Controlled Trial ◽  
Performance Status ◽  
Objective Response ◽  
Metastatic Breast ◽  
High Sensitivity ◽  
Controlled Study ◽  
Ecog Performance Status ◽  
Baseline Values

Abstract Background: Preclinical studies support anticancer activity of statins, however, the existing clinical evidence are inconsistent and not definitive. Our study aimed at evaluating a postulated cancer chemo sensitizing effect of statin (simvastatin) in a cohort of metastatic breast cancer (MBC) patients.Methods: We designed a prospective, single-centered, randomized, double blinded, and placebo controlled trial that encompassed MBC patients with an ECOG Performance Status scale ≤2 and undergoing a chemotherapy course consisting of carboplatin and vinorelbine at Al-Baironi Hospital, Damascus, Syria. Patients were enrolled between August 2011 and July 2012, and randomly allocated to receive a 15-day course of either simvastatin (40 mg) or placebo at the day -7 of each chemotherapy cycle. Primary endpoints were objective response rate (ORR) and toxicity, and secondary endpoint was overall survival (OS).Results: Eighty-Two patients met the inclusion criteria and consented. ORR (35% vs. 32.5%) and predominant toxicity; grade≥3 neutropenia (occurred in 30% vs. 40% of the patients) were not significantly different between simvastatin and placebo groups, respectively. Over a median follow-up of 44 months (range, 10-60), median OS was 15 months in simvastatin group and 17 in placebo group (Hazard ratio (HR)=1.16, 95% CI (0.70-1.91), P =0.57). Elevated baseline values of high-sensitivity C-reactive protein (hsCRP >10 mg/l), lactate dehydrogenase (LDH >480 U/L) and chemotherapy being ≥2 nd line significantly associated with shorter OS for the total cohort in both univariate and multivariate analyses. Conclusions: Our data prove a safe profile of simvastatin at 40 mg per day combined with carboplatin and vinorelbine in MBC patients, but without any beneficial increase of tumor sensitivity to chemotherapy. Moreover, we demonstrated a strong clinical advantage of baseline values of hsCRP and LDH as useful prognostic tools in MBC patients. Trial registration: Damascus University / 15073/. Registered on December 28, 2010.

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