Event-free survival analysis of the prospectively randomized phase III ETNA study with neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) followed by anthracycline regimens in women with HER2-negative high-risk breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 515-515 ◽  
Author(s):  
Luca Gianni ◽  
Mauro Mansutti ◽  
Antonio Anton ◽  
Lourdes Calvo Martínez ◽  
Giancarlo Bisagni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statistical Significance ◽  
Secondary Endpoint ◽  
Phase Iii ◽  
Primary Therapy ◽  
Event Free Survival ◽  
Open Label ◽  
Serious Adverse Events ◽  
Free Survival ◽  
Luminal B

515 Background: The ETNA study showed that substituting P with nab-P did not significantly increase the overall rate of pathological complete response (pCR) (P 18.6%, nab-P 22.5%, p = 0.19). The multivariate analysis revealed that tumor subtype (triple negative vs luminal B-like) was the most significant factor (OR 4.85) influencing treatment outcome (Gianni L et al, JAMA Oncol 2018). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to nab-P 125 mg/m2 (346 patients) or P 90 mg/m2 (349 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen as per investigator choice. The primary endpoint was pCR (absence of invasive cells in breast and nodes). A secondary endpoint is event-free survival (EFS) defined as the time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast cancer) after surgery or death due to any cause. Results: The ITT analysis of the secondary endpoint EFS at 5 years is reported below: Clinical trial information: NCT01822314. Overall 5-year survival was 84.8% after P and 87.3% for nab-P. No serious adverse events were documented during the follow-up. Conclusions: The improved 5-year EFS after nab-P failed to reach statistical significance (unadjusted P = 0.245). In the analysis by subgroup the numerical improvement was almost exclusively observed in luminal B and not in TN tumors. So far the data do not support substitution of P with nab-P in the schedule and doses adopted in the ETNA trial. Additional analyses will be based on ongoing molecular studies.[Table: see text]

A randomized phase III study to determine the efficacy of capecitabine in addition to a taxane and bevacizumab as first-line therapy in patients with metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1082-1082 ◽  
Author(s):  
Hans-Joachim Lueck ◽  
Kristina Luebbe ◽  
Joachim Bischoff ◽  
Nicolai Maass ◽  
Gabriele Feisel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Locally Advanced ◽  
Sample Size Calculation ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Open Label ◽  
Serious Adverse Events ◽  
Line Therapy

1082 Background: Conventional chemotherapy combined with novel molecular targeted agents has been proven effective and tolerable in metastatic breast cancer (MBC). Taxanes (T) plus bevacizumab (B) and T plus capecitabine (X) showed a benefit in progression free survival (PFS) compared to T alone. Life-threatening or highly symptomatic situations require poly-chemotherapies in MBC patients; therefore a combination of all 3 drugs appears reasonable. Methods: TABEA (NCT01200212) is a prospective, randomized, open label, phase III trial comparing T plus B +/- X as 1st-line therapy in MBC. Patients with histologically confirmed HER2- locally advanced or MBC were included. All patients received T (paclitaxel 80 mg/m2 i.v. d1,8,15 q22 or docetaxel 75 mg/m2 i.v. d1 q22) and B (15 mg/kg i.v. d1 q22) (TB) and were randomized to X (1800 mg/m² daily d1-14 q22) in addition and concurrently to TB (TBX) or TB alone. Randomization was stratified by receptor status, planned taxane, and disease free interval (≤ or >12 months). Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (CR, PR, stable disease ≥ 24 weeks), 3yr overall survival, PFS in patients ≥ 65 years, toxicity, and compliance. Sample size calculation assumed a PFS of 10 and 13.3 months for TB and TBX, respectively (HR=0.75) requiring 432 patients and 386 events with 2-sided α=0.05 and β=0.2. Interim analysis was planned after 25% of required events (n=96). Results: Planned interim futility and safety analyses after 100 documented events in 202 patients have shown no efficacy benefit and higher toxicity in the TBX arm. For PFS, HR=1.061, 95% CI (0.715, 1.576) was observed, futility boundary was crossed. Overall grade 3-4 adverse events (e.g., thrombopenia, diarrhea, hand-foot-syndrome) (72.3 vs. 57.4%, p=0.039)and serious adverse events (40.6 vs. 24.8%, p=0.016) rates were higher for TBX after 16.3 months median follow up. There were 6 deaths in the TBX vs. 1 in the TB arm. Recruitment and therapy were stopped on 5th Oct 2012 following the advice from the IDMC. Conclusions: TABEA failed to show an improvement using the 3 drug regimen TBX in high-risk MBC patients. Clinical trial information: NCT 01200212.

Results of a Prospective Randomised Open Label Phase III Study Comparing Rituximab Plus Mitoxantrone, Chlorambucile, Prednisolone Chemotherapy (R-MCP) Versus MCP Alone in Untreated Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) and Mantle-Cell-Lymphoma (MCL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 584-584 ◽  
Author(s):  
Michael Herold ◽  
Rita Pasold ◽  
Stefanie Srock ◽  
Sabine Neser ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Phase Iii ◽  
Published Data ◽  
Event Free Survival ◽  
Serious Adverse Events ◽  
Free Survival ◽  
Phase Ii Studies

Abstract Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p<0,0001). Results were even more impressive in the subgroup of FL pts (n=201) with an overall RR of 92,4% and a CR rate of 49,5% for R-MCP versus 75% and 25% for MCP alone respectively (p<0,0001). In the overall group event free survival (EFS) was significantly prolonged for pts receiving R-MCP vs MCP alone (p<0,001). Median EFS for MCP was 19 months, at this time point EFS for R-MCP was 73%. In FL pts the median EFS for MCP is 19 months too and EFS was 86% for R-MCP at this point. 2-year EFS for all pts was 69% for R-MCP versus 44% for MCP; for FL pts the respective 2-year EFS was 83% for R-MCP and 43% for MCP (p’s<0,0001) (Kaplan Maier estimates). These results compare favourably with the recntly published data of immunochemotherapy for treatment of NHL or MCL. The results from our study confirm the superiority of a combination of rituximab and chemotherapy in the first- line treatment of indolent NHL, primarily follicular lymphoma. The CR rates achieved with the R-MCP regimen are impressive, especially since stricter response criteria were used. In summary we conclude, that the addition of rituximab to MCP chemotherapy improves significantly the outcome of pts with indiolent NHL and MCL.

Intense Dose-Dense Sequential Chemotherapy With Epirubicin, Paclitaxel, and Cyclophosphamide Compared With Conventionally Scheduled Chemotherapy in High-Risk Primary Breast Cancer: Mature Results of an AGO Phase III Study

2010 ◽  
Vol 28 (17) ◽  
pp. 2874-2880 ◽  
Author(s):  
Volker Moebus ◽  
Christian Jackisch ◽  
Hans-Joachim Lueck ◽  
Andreas du Bois ◽  
Christoph Thomssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Primary Breast Cancer ◽  
Survival Rates ◽  
Phase Iii ◽  
Axillary Lymph Nodes ◽  
Axillary Lymph ◽  
Event Free Survival ◽  
Free Survival ◽  
Dose Dense

Purpose Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy. We compared intense dose-dense (IDD) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer. Patients and Methods In this randomized, phase III trial, a total of 1,284 eligible patients with four or more involved axillary lymph nodes were randomly assigned to receive IDD sequential epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks. The primary end point was event-free survival (EFS). Results At a median follow-up of 62 months, 5-year event-free survival rates were 62% in the conventional arm and 70% in the IDD-ETC arm, representing a 28% reduction of the relative risk of relapse (P < .001). This benefit was independent of menopausal, hormone receptor, or human epidermal growth factor receptor 2 status. The 5-year overall survival rates were 77% versus 82%, representing a 24% reduction of the relative risk of death (P = .0285). IDD therapy was associated with significantly more nonhematologic and hematologic toxicities, but no treatment-related death occurred. Four occurrences of acute myeloid leukemia or myelodysplastic syndrome (MDS) were observed in the IDD-ETC arm. No severe congestive heart failure was reported. Conclusion IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes.

Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial

2017 ◽  
Vol 35 (23) ◽  
pp. 2639-2646 ◽  
Author(s):  
Bent Ejlertsen ◽  
Malgorzata K. Tuxen ◽  
Erik Hugger Jakobsen ◽  
Maj-Britt Jensen ◽  
Ann Soegaard Knoop ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Disease Free Survival ◽  
Normal Breast ◽  
Phase Iii ◽  
Open Label ◽  
Distant Disease ◽  
Free Survival ◽  
Open Label Phase ◽  
Disease Free

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non–anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease–free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease–free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

scholarly journals Phase III Study of Enzastaurin Compared With Lomustine in the Treatment of Recurrent Intracranial Glioblastoma

2010 ◽  
Vol 28 (7) ◽  
pp. 1168-1174 ◽  
Author(s):  
Wolfgang Wick ◽  
Vinay K. Puduvalli ◽  
Marc C. Chamberlain ◽  
Martin J. van den Bent ◽  
Antoine F. Carpentier ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Objective Response ◽  
Progression Free Survival ◽  
Well Being ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Serious Adverse Events ◽  
Who Grade

PurposeThis phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).Patients and MethodsPatients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m2, day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025.ResultsEnrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P ≤ .001).ConclusionEnzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.

Impact of concurrent (CON) and sequential (SEQ) radiotherapy (RT) with adjuvant aromatase inhibitors (AI) in early-stage breast cancer (EBC): NCIC CTG MA.27.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Abdullah Khalaf Altwairgi ◽  
Wendy Parulekar ◽  
Judy-Anne W. Chapman ◽  
Lois E. Shepherd ◽  
Kathleen I. Pritchard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Annual Meeting ◽  
Aromatase Inhibitors ◽  
Early Stage ◽  
Hazard Ratio ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Sensitivity Analyses ◽  
Event Free Survival ◽  
Free Survival

500 Notice of Retraction: "Impact of concurrent (CON) and sequential (SEQ) radiotherapy (RT) with adjuvant aromatase inhibitors (AI) in early-stage breast cancer (EBC): NCIC CTG MA.27." Abstract 500, published in the 2012 Annual Meeting Proceedings Part I, a supplement to the Journal of Clinical Oncology, has been retracted by Wendy Parulekar, MD, and Timothy J. Whelan, BM, BCh, MSc, on behalf of all authors of the abstract. The abstract concluded by suggesting that concurrent administration of an AI during the period of radiation may improve event-free survival as compared to commencing AI after completing radiation therapy. After submitting the abstract for the 2012 ASCO Annual Meeting, the authors identified issues associated with the statistical analysis of this research, which led them to reanalyze the data and in so doing, they reached different conclusions from those described in the abstract. As opposed to the abstract, which reports a hazard ratio (HR) of AI administration that is concurrent with RT vs. sequential to RT of 0.78 (p=0.001), they have determined that using a more appropriate analysis, the hazard ratio is 0.84 (p=0.13). Multiple sensitivity analyses have been performed and yield hazard ratios of 0.81-0.84 and p values of 0.07 to 0.13. In view of these findings, the conclusions reported in the abstract cannot be supported. Background: Optimal timing of administration of adjuvant (adj) RT and AI in EBC is unknown. Methods: MA.27 was a phase III RCT of exemestane to anastrozole in postmenopausal women with hormone receptor positive EBC (Goss et al. Cancer Res. 70(24, Suppl):75s, 2010). The final trial database was used for this retrospective analysis. Median follow-up was 4.1 years. MA.27 patients received CON-AI [any overlap with AI; 4233 (57%) patients], SEQ-AI [RT preceded AI, no overlap with AI; 1010 (14%) patients] and No RT [AI only; 2128 (29%) patients]. Outcome measures for this analysis were: event free survival (EFS; time to locoregional or distant disease recurrence, new primary BC, or death from any cause), locoregional recurrence (LRFS), distant recurrence (DDFS) and overall survival (OS). RT groups were compared univariately (uni) with stratified log-rank tests, and multivariately (multi) with step-wise stratified Cox regression adjusted by stratification factors: nodal status, adj chemotherapy (chemo), celecoxib, aspirin, and trastuzumab. Results: 7371 eligible women received AI; were included in the analysis; and 71% (5243) received adj RT. CON-AI and SEQ-AI groups were comparable by median age (63 v 63), proportion T1 tumours (75% v 75 %), and mastectomy rate (10% v 11%). The frequency of axillary dissection for CON-AI and SEQ-AI was 48% v 44%, proportion N0 was 73% v 69%, and proportion receiving adj chemo 29% v 41%. CON-AI had similar uni results to SEQ-AI: EFS, HR=0.86, p=0.20; LRFS, HR=0.82, p=0.51; DDFS, HR=0.92, p=0.59; and OS, HR=1.04, p=0.80. In multi analyses, CON-AI had better EFS than SEQ-AI patients [stratified HR of CON-AI to SEQ-AI 0.78 (0.66 – 0.91), p=0.001]; as well, age≥70 (p<0.0001), ECOG PS≥1 (p<0.0001), L-sided tumours (p=0.02), T2-T4 (p<0.0001), N2/N3 (p<0.0001), and no adj chemo (p=0.01) had significantly shorter EFS. There was no multi difference between CON-AI and SEQ-AI for LRFS (p=0.50), DDFS (p=0.72), or OS (p=0.85). Conclusions: Patients receiving CON-AI had significantly better EFS than SEQ-AI suggesting timing of administration of AI and RT may affect patient outcomes. Further research is necessary to confirm these findings.

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