Phase Ib trial of gemcitabine with yttrium-90 in patients with hepatic tumors of pancreatobiliary origin.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 460-460
Author(s):  
Hyun S Kim ◽  
Juan C. Camacho ◽  
Bassel F. El-Rayes
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Objective Response Rate ◽  
Response Rate ◽  
Liver Tumors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Hepatic Tumors ◽  
Free Survival ◽  
Yttrium 90

460 Background: The rationale for combining Gemcitabine (G) with Yttrium-90 (Y90) is based on G being a potent radio sensitizer and activity of Y90 against liver tumors of pancreatobiliary histology. Therefore, a safety and efficacy trial of adding G to Y90 is required. Methods: Eligibility: Chemo-naïve patients with histologic diagnosis of unresectable PC or CC with liver predominant disease. Design: Open label phase I design with 3+3 G dose escalation. Induction G on Day 1 followed by Y90 on Day 2 and subsequent pre-assigned dose levels of G until week 12. Primary objective: To determine the maximal tolerated dose of G that can be used in combination with Y90. Secondary objectives: To characterize the toxicity, evaluate hepatic progression free survival (HPFS); determine tumor response rate using RECIST and PERCIST criteria; determine the progression free survival (PFS) and overall survival (OS). Correlative Imaging: 18-FDG PET/CT with contrast at baseline and 12 weeks. Results: 14 patients were recruited and 8 met the inclusion criteria. Seven out of eight patients tolerated the dose escalation regime of G (dose level 1-400 and dose level 2-600mg/m2). All the patients developed grade 1 toxicities (Hepatobiliary 25%, Bone marrow 25%, Fatigue 100%). Three patients (37.5 %) had grade 2 hepatobiliary toxicity and one patient (12.5 %) had grade 3 hepatobiliary toxicity, which required short-term hospitalization. No radiation pneumonitis, gastrointestinal ulceration, or procedure-related mortality occurred. Six patients (75%) developed grade 1 toxicity (fatigue). All of the patients had SD in the liver by RECIST; the objective response rate was 62.5% by PERCIST (CR12.5%, PR50%, SD25% PD12.5%). Overall objective response rate was 0% by RECIST (SD62.5%, PD37.5%); and 50% for PERCIST (CR12.5%, PR37.5%, SD12.5%, PD37.5%). The median OS from diagnosis was 13.8 months (95% CI, 9.65 to 26.29 months) and from Y90 therapy 10.9 months (95% CI, 6.47 to 22.39 months). PFS was 6.92 months (95%CI, 4.37-16.5 months) and HPFS of 8.72 months (95%CI, 4.48-19.36 months). Conclusions: In patients with hepatic tumors of pancreatobiliary origin, Gemcitabine at 600mg/m2 with Y90 therapy appears to be a viable and safe therapy. Clinical trial information: NCT01434459.

Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis

2019 ◽  
Vol 26 (6) ◽  
pp. 1331-1342
Author(s):  
Irena Ilic ◽  
Sandra Sipetic ◽  
Jovan Grujicic ◽  
Milena Ilic
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Meta Analysis ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival

Introduction Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. Material and methods A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. Results The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79–0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69–1.01), p = 0.06 and OR = 1.46 (95% CI 0.90–2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16–66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23–3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28–1.87, p < 0.00001). Conclusions The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial

2018 ◽  
Vol 36 (19) ◽  
pp. 1973-1980 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Barbara Eichhorst ◽  
Johannes Schetelig ◽  
Peter Hillmen ◽  
John F. Seymour ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Median Time ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Free Survival

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10−4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10−4 was achieved in this high-risk population.

Clinical effectiveness of bevacizumab in patients with recurrent brain tumours: A population-based evaluation

2016 ◽  
Vol 24 (1) ◽  
pp. 33-36 ◽  
Author(s):  
Mário L de Lemos ◽  
Adeline Markarian ◽  
Esther Chan ◽  
Kimberly Schaff ◽  
Susan Walisser
Keyword(s):  
Overall Survival ◽  
Disease Progression ◽  
Brain Tumour ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
The United States ◽  
Free Survival ◽  
Recurrent Brain Tumour

Background Bevacizumab is an antiangiogenic agent active in patients with recurrent malignant gliomas. However, evidence for its clinical efficacy is relatively limited so that bevacizumab is approved for this indication in Canada and the United States, but not in the European Union. We reviewed the effectiveness of bevacizumab in patients with recurrent brain tumour using a large population database. Methods This was a retrospective, multicentre, study conducted at the BC Cancer Agency, a public cancer care organisation for the residents of the Canadian province of British Columbia. Cases were identified from the provincial registry and drug database. Patients were eligible if they were treated with bevacizumab with or without lomustine or etoposide for recurrent brain tumour between April 2011 and March 2014. The primary end points were progression-free survival. Secondary endpoints were overall survival and objective response rate. Results A total of 160 patients were included, with a median age of 55 years. The most common diagnosis was glioblastoma multiforme (70.6%), followed by oligodendroglioma (10.6%). Half of the patients had prior metronomic dosing of temozolomide. The median duration of therapy was 3 months. The median progression-free survival was 4.0 months and the 6-month progression-free survival was 29.4%. The median overall survival was 7 months and the 9-month and 12-month overall survival was 28.1% and 20.6%, respectively. The objective response rate was 23.1%. The most common documented reason for bevacizumab discontinuation was disease progression (66.9%), followed by toxicity (6.9%). Conclusions Bevacizumab therapy seems to be effective in delaying disease progression in patients with recurrent brain tumour, but with limited benefits on the overall survival, when used outside the clinical trial setting.

A dose attenuated schedule of irinotecan and capecitabine in combination with celecoxib in advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3584-3584
Author(s):  
B. F. El-Rayes ◽  
A. F. Shields ◽  
U. Vaishampayan ◽  
L. K. Heilbrun ◽  
M. M. Zalupski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Chemotherapeutic Agents ◽  
Free Survival ◽  
Study Results ◽  
Cox 2

3584 Background: The cyclooxygenase-2 (COX-2) enzyme is overexpressed in the majority of colorectal cancers. Inhibition of the COX-2 enzyme can sensitize colorectal cancer cells to the apoptotic effects of chemotherapeutic agents and block angiogenesis. This phase II study was undertaken to determine the effects of adding celecoxib to a dose attenuated irinotecan and capecitabine regimen. Methods: The primary objective was to estimate the objective response rate of patients with metastatic colorectal cancer treated with irinotecan, capecitabine, and celecoxib. Previously untreated patients, except for adjuvant therapy, with metastatic colorectal adenocarcinoma were eligible for this study. Patients received irinotecan 70 mg/m2 (over 30 minutes) on days 1 and 8, and capecitabine 2,000 mg/m2/day from day 1 to 14 of a 21-day cycle. Celecoxib was administered at a dose of 400 mg twice-daily starting on day -7 until termination from study. Results: A total of 51 patients (median age 58 years) have been enrolled on the study. The results presented are for the first 48 patients registered to the study. Median performance status was 1. A median number of 5.5 cycles (range 0- 18) were administered. In an intention to treat analysis, objective response rate was 50%. The median progression free survival was 6.9 months (90%CI; 4.7–8.2). Median survival is ≥19.4 months. No treatment related deaths were observed. The only grade 4 toxicity was diarrhea in 2 (4%) patients. Grade 3 toxicities were diarrhea (33%), hand-foot syndrome (8%), nausea (13%), vomiting (8%) and neutropenia (12%). Conclusion: Lowering the dose intensity of irinotecan in this study did not appear to compromise the treatment outcome and markedly improved the therapeutic index of this combination. Celecoxib can be safely administered in combination with irinotecan and capecitabine. Based on the observed progression free survival and response rate, the regimen has promising activity. No significant financial relationships to disclose.

scholarly journals Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629)

2020 ◽  
Vol 38 (25) ◽  
pp. 2916-2925 ◽  
Author(s):  
Jean-Jacques Grob ◽  
Rene Gonzalez ◽  
Nicole Basset-Seguin ◽  
Olga Vornicova ◽  
Jacob Schachter ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Adverse Events ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Free Survival ◽  
Duration Of Response

PURPOSE Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort—locally advanced and R/M—phase II KEYNOTE-629 study. PATIENTS AND METHODS Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety. RESULTS At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; ‘+’ refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy. CONCLUSION Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.

Results of a phase II study of capecitabine-based doublets in the treatment of metastatic triple-negative breast cancer (mTNBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11538-e11538
Author(s):  
Ying Fan ◽  
Binghe Xu ◽  
Yuqian Liao ◽  
Fei Ma ◽  
Peng Yuan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Free Survival ◽  
Metastatic Setting ◽  
Secondary Endpoints

e11538 Background: It is extremely important to identify proper cytotoxic agents for TNBC which had limited choices except chemotherapy. Capecitabine are well established as a major chemotherapeutic agent in metastatic setting. The efficacy of capecitabine-based chemotherapy has not been prospectively studied in TNBC and data remains scant. This study was designed to investigate the efficacy of capecitabine-based doublets in the treatment of metastatic TNBC. Methods: Eligible metastatic TNBC women with measurable diseases were recruited to receive either TX regimen (docetaxel 75mg/m2 iv d1 plus capecitabine 1000mg/m2 bid, d1-14,q3w) or NX regimen (vinorelbine 25mg/m2 iv d1, 8 plus capecitabine 1000mg/m2 bid, d1-14, q3w) at the discretion of physicians for up to 6 cycles, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate and secondary endpoints included progression free survival (PFS), overall survival (OS). Results: 45 mTNBC patients, 27 in TX and 18 in NX were recruited, mostly (73.3%) as 1st line and the remaining as the 2nd line. The total objective response rate was 20.0% and clinical benefit rate was 62.2%. After a median follow-up of 28 months, PFS was 5.2 months (95%CI, 4.1-6.3mons) and OS was 18.2months (95%CI, 8.7-27.7mons). Almost half of the patients (22/45) progressed during treatment or within one month of the treatment discontinuation. PFS was significantly longer if patients got CR/PR (9.6 vs 4.3mons, P=0.015). When comparing two doublets, the response rate was numerically but not statistically lower in TX group than in NX group (14.8% vs 27.8%, P=0.449). Similarly, no difference was found in either PFS (4.9 vs 5.2 mons, P=0.483) or OS (21.5 vs 18.3 mons, P=0.964) between two regimens. Conclusions: Although the overall survival seems to be reasonable, efficacy of capecitabine-contained TX or NX regimen was relatively poor in terms of tumor remission and progression free survival in mTNBC patients, suggesting capecitabine may have limited potency in this subtype. These two combinations may be considered to be acceptable but may not be recommended as prior choice for mTNBC patients.

Objective response rate and progression-free survival as surrogate endpoints for overall survival and the impact of crossover and unbalanced post-progression treatments: A systematic review and meta-analysis in second- and further-line therapy of advanced non-small cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20609-e20609
Author(s):  
Boris Pfeiffer ◽  
Mahmoud Hashim ◽  
Robert Bartsch ◽  
Maarten Postma ◽  
Bart Heeg
Keyword(s):  
Overall Survival ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Absolute Difference ◽  
Surrogate Endpoints ◽  
Free Survival ◽  
Line Therapy ◽  
The Impact

e20609 Background: Correlations between overall survival (OS) and objective response rate (ORR) or progression-free survival (PFS) are poor. We aimed to evaluate the impact of crossover and unbalanced subsequent treatments on ORR and PFS as surrogate endpoints for OS in patients with advanced NSCLC receiving second- and further-line therapy. Methods: A systematic literature review of randomized clinical trials of systemic treatment for patients with stage IIIB/IV NSCLC receiving second- and further-line therapy was performed. Weighted (by trial size) linear regression models were fitted with the absolute difference in ORR or median PFS as an independent variable and the absolute difference in median OS as a dependent variable. The analysis was repeated in predefined subsets based on crossover and balance of post-progression therapies. Surrogate threshold effect (STE) was estimated using prediction intervals. Results: 146 trials (43,061 patients) fulfilled the eligibility criteria. In all treatment arms, the mean ORR, median PFS, and median OS were 12.2% (standard deviation [SD] 11.2%), 3.2 months (SD 1.3), and 9.6 months (SD 4.1), respectively. ORR and PFS had very weak (R = 0.181; 95% CI: 0.016-0.337) and weak (R = 0.254; 95% CI: 0.074-0.418) relationships, respectively, with OS. However, within trials that did not allow crossover and reported balanced post-progression treatments, ORR and PFS had moderate (R = 0.528; 95% CI: 0.081-0.798) and strong (R = 0.778; 95% CI: 0.475-0.916) relationships, respectively, with OS. STE estimation indicated that trials that show statistically significant treatment effect size of ≥41.0% ORR or ≥4.15 median PFS months can be expected to show significant OS benefit with sufficient certainty. Conclusions: Surrogacy of ORR and PFS for OS might be better estimated in trials that do not allow crossover and report balanced post-progression treatments. Presented STE calculation can be used to estimate the expected effect on OS when either ORR or PFS are used as primary endpoints.

scholarly journals Immune Checkpoint Inhibitors in Advanced Acral Melanoma: A Systematic Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Qingyue Zheng ◽  
Jiarui Li ◽  
Hanlin Zhang ◽  
Yuanzhuo Wang ◽  
Shu Zhang
Keyword(s):  
Systematic Review ◽  
Combination Therapy ◽  
Objective Response Rate ◽  
Median Overall Survival ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Therapeutic Effects ◽  
Free Survival

IntroductionAcral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM.MethodsThis systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles.ResultsThis systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies.ConclusionsICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.

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