Assessing the translational value of pre-clinical studies for clinical response rate in oncology: an exploratory investigation of 42 FDA-approved small-molecule targeted anticancer drugs

2020 ◽  
Vol 85 (6) ◽  
pp. 1015-1027
Author(s):  
Wenying Angela Liu ◽  
Li Yu ◽  
Peter N. Morcos ◽  
Francois Mercier ◽  
Barbara J. Brennan
Keyword(s):  
Clinical Response ◽  
Anticancer Drugs ◽  
Small Molecule ◽  
Clinical Studies ◽  
Response Rate ◽  
Clinical Response Rate ◽  
Exploratory Investigation

scholarly journals Efficacy and Safety of Aidi Injection Combined with Transcatheter Arterial Chemoembolization on Primary Hepatic Carcinoma: A Systematic Review and Meta-Analysis

2018 ◽  
Vol 2018 ◽  
pp. 1-14
Author(s):  
Weihao Chen ◽  
Yurong Wang ◽  
Qiuer Liang ◽  
Yunfei Cai ◽  
Xudong Chen ◽  
...  
Keyword(s):  
Clinical Response ◽  
Transcatheter Arterial Chemoembolization ◽  
Response Rate ◽  
Clinical Response Rate ◽  
Efficacy And Safety ◽  
Hepatic Carcinoma ◽  
Primary Hepatic Carcinoma ◽  
Significant Difference ◽  
Aidi Injection ◽  
Arterial Chemoembolization

Objectives. To evaluate the efficacy and safety of Aidi injection (ADI) combined with transcatheter arterial chemoembolization (TACE) for primary hepatic carcinoma (PHCC). Methods. We conducted a literature search in EMBASE, PubMed, CENTRAL, MEDLINE, CNKI, Wanfang, and VIP databases from the earliest possible year to April 2018. Randomized controlled trials (RCTs) involving ADI combined with TACE versus TACE alone for patients with PHCC were included. The Cochrane Risk of Bias tool was applied for quality assessment. Results. 22 studies involving 1611 participants were included. The clinical response rate (RR = 1.28, 95% CI: 1.17-1.40; P < 0.00001), KPS score (RR = 1.78, 95% CI: 1.59-2.00; P < 0.00001), survival rate (RR = 1.27, 95% CI: 1.16-1.39; P < 0.00001), immune function (MD = 1.24, 95% CI: 0.98-1.51; P < 0.00001), and adverse effects (RR = 0.62, 95% CI: 0.57-0.68; P < 0.00001) of ADI plus TACE showed significant difference when compared with TACE alone. Conclusions. ADI combined with TACE in the treatment of PHCC improved the clinical response rate and safety compared to TACE alone. However, due to poor methodological quality of many of the included RCTs, more rigorously designed and large-scale RCTs are warranted to examine this beneficial effect in the future.

scholarly journals A Phase II Study of Sequential Treatment with Anthracycline and Taxane Followed by Eribulin in Patients with HER2-negative, Locally Advanced Breast Cancer (JBCRG-17)

2021 ◽  
Author(s):  
Ippei Fukada ◽  
Yoshinori Ito ◽  
Naoto Kondo ◽  
Shoichiro Ohtani ◽  
Masaya Hattori ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Clinical Response ◽  
Phase Ii ◽  
Response Rate ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Clinical Response Rate ◽  
Sequential Administration

Abstract PurposeThe sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy (NAC) has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC.MethodsIn this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative.ResultsA preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease (cPD) rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade >3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%)ConclusionSequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.

A phase II open label, single arm study to evaluate the efficacy of pembrolizumab for leukoplakia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS10606-TPS10606
Author(s):  
Ashleigh Porter ◽  
Audrey J. Zeh ◽  
Thu Ly ◽  
Alyssa Serna ◽  
Arturo Villanueva ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase Ii ◽  
Response Rate ◽  
Two Dimensions ◽  
Premalignant Lesions ◽  
Clinical Response Rate ◽  
Clinical Impression ◽  
Severe Dysplasia ◽  
Open Label ◽  
Recurrence Rates

TPS10606 Background: The presence of pre-cancerous oral lesions such as leukoplakia or erythroleukoplakia are known risk factors for the development of squamous cell carcinoma of the head and neck (SCCHN), however preventative agents have not yet shown clinical benefit. The risk of malignant transformation varies but has been quoted as high as 36% in some studies. While the primary mode of treatment of these lesions is largely surgical, recurrence rates are high. Pembrolizumab is a potent and selective humanized monoclonal antibody that is designed to directly block the interaction between PD-1 and PD-L1 (as well as PD-L2) that is currently FDA-approved for treatment of SCCHN. We have hypothesized that the treatment of oral premalignant lesions with pembrolizumab would be an effective and well-tolerated strategy to prevent transformation to invasive cancer. Methods: This study is an open-label, phase II study that will accrue 26 patients with leukoplakia, erythroleukoplakia, or proliferative verrucous leukoplakia with documented moderate to severe dysplasia or carcinoma in situ to be treated with pembrolizumab 200mg every 3 weeks for a total of 6 months. Patients must have visible and measurable lesions that will be both photographed and measured in two dimensions at each visit from the start of treatment until 12 months post-enrollment. Biopsies will be required at diagnosis and following the final treatment, with an optional biopsy following cycle 2 and at progression of disease. Major exclusion criteria include patients with mild dysplasia or hyperplasia, prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of Day 1 of study, or patients with a known additional malignancy that is active. Patients will also be excluded if they have received anti-PD-1, anti-PD-L1 or anti-PD-L2 treatments in the past. The primary objective is clinical response rate at 6 months, and will be quantified as the percentage of patients with a complete response (CR) and partial response (PR) at 6 months. A CR is defined as complete resolution by visual inspection for 4 weeks of more and a PR is defined as 50% or greater reduction of the product of the 2 dimensions of a single lesions or the sum of all lesions. Progressive disease (PD) is defined as unequivocal increase (greater than or equal to 5mm in one dimension and greater than 20% increase) or the development of new lesions. Secondary objectives will include histologic response rate at 6 months, change in clinical impression based on photographs, clinical response rate at 9 and 12 months, and toxicity. Additional exploratory objectives will include PD-L1 expression in leukoplakia lesions as well as p16 expression, presence of tumor infiltrating lymphocytes, and immunohistochemical as well as RNA sequencing gene expression profiling which may allow for the identification of novel biomarkers. Enrollment began in June 2019 and is ongoing. Clinical trial information: NCT03603223 .

Abstract 2600: Refinement of the MR Diffusion-perfusion Mismatch Concept for Thrombolytic Patient Selection: Insights from the Desmoteplase In Acute Stroke Trials

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Steven Warach ◽  
Yasir Al-Rawi ◽  
Anthony J Furlan ◽  
Jochen B Fiebach ◽  
Max Wintermark ◽  
...  
Keyword(s):  
Clinical Response ◽  
Patient Selection ◽  
Effect Size ◽  
Response Rate ◽  
Time Window ◽  
Placebo Response ◽  
Placebo Treatment ◽  
Pooled Analysis ◽  
Selection Strategy ◽  
Clinical Response Rate

The DIAS-2 study was the only large, randomized intravenous thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore a reevaluation of the penumbra selection strategy is warranted. In post-hoc analyses we assessed the relationships of MRI-measured lesion volumes to clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch to the clinical effect of desmoteplase in DIAS-2 (MRI-selected patients) and in pooled data from MRI-selected 90- and 125-μg/kg dose groups in DIAS, DEDAS, and DIAS-2. In DIAS-2, lesion volumes correlated with NIHSS at both baseline and final time points (P<0·0001), and lesion growth was inversely related to good clinical outcome (P=0.004). In the pooled analysis, treatment was associated with 47% clinical response rate in desmoteplase (n=143) versus 34% in placebo (n=73; P=0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size, preferentially decreasing the placebo-response rate. There was a trend of statistically significant differences in effect size in ≤60 mL versus >60 mL baseline mismatch subgroups (P=0.083). The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% CI, 1.16-6.94, P=0.023) for a MMV >60 mL. Increasing the minimum NIHSS for inclusion did not affect treatment effect size. Pooled across all desmoteplase trials, penumbral selection by MRI diffusion-perfusion mismatch favored desmoteplase clinical benefit, especially for larger MMV. Based on these results, a three-fold reduction in future trial sample size requirements would be achieved using a criterion of baseline MMV >60 mL over any visible mismatch. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later-time-window thrombolytic trials.

scholarly journals Tedizolid Versus Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-Analysis

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 137 ◽  
Author(s):  
Shao-Huan Lan ◽  
Wei-Ting Lin ◽  
Shen-Peng Chang ◽  
Li-Chin Lu ◽  
Chien-Ming Chao ◽  
...  
Keyword(s):  
Clinical Response ◽  
Response Rate ◽  
Meta Analysis ◽  
Study Drug ◽  
Adult Patients ◽  
Skin Structure Infection ◽  
Cochrane Library ◽  
Clinical Response Rate ◽  
Skin Structure ◽  
Structure Infection

This meta-analysis aims to assess the efficacy and safety of tedizolid, compared to linezolid, in the treatment of acute bacterial skin and skin structure infection (ABSSSI). PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid Medline and Embase databases were accessed until 18 July 2019. Only randomized controlled trials (RCTs) comparing the efficacy of tedizolid with linezolid for adult patients with ABSSSIs were included. The outcomes included the clinical response, microbiological response, and risk of adverse events (AEs). A total of four RCTs involving 2056 adult patients with ABSSSI were enrolled. The early clinical response rate was 79.6% and 80.5% for patients receiving tedizolid and linezolid, respectively. The pooled analysis showed that tedizolid had a non-inferior early clinical response rate to linezolid (odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.77–1.19, I2 = 0%). The early response rate was similar between tedizolid and linezolid among patients with cellulitis/erysipelas (75.1% vs. 77.1%; OR = 0.90, 95% CI = 0.64–1.27, I2 = 25%), major cutaneous abscess (85.1% vs. 86.8%; OR = 0.93, 95% CI = 0.42–2.03, I2 = 37%) and wound infection (85.9% vs. 82.6%; OR = 1.29, 95% CI = 0.66–2.51, I2 = 45%). For methicillin-resistant Staphylococcus aureus patients, tedizolid had a favorable microbiological response rate of 95.2% which was comparable to linezolid (94%) (OR = 1.19, 95% CI = 0.49–2.90, I2 = 0%). In addition to the similar risk of treatment-emergent AEs (a serious event, the discontinuation of the study drug due to AEs and mortality between tedizolid and linezolid), tedizolid was associated with a lower risk of nausea, vomiting and abnormal neutrophil count than linezolid. In conclusion, once-daily tedizolid (200 mg for six days) compared to linezolid (600 mg twice-daily for 10 days) was non-inferior in efficacy in the treatment of ABSSSI. Besides, tedizolid was generally as well tolerated as linezolid, and had a lower incidence of gastrointestinal AEs and bone marrow suppression than linezolid.

Cisplatin, carboplatin, and cyclophosphamide combination chemotherapy in advanced-stage ovarian carcinoma: an Eastern Cooperative Oncology Group pilot study.

1991 ◽  
Vol 9 (10) ◽  
pp. 1793-1800 ◽  
Author(s):  
J Grem ◽  
P O'Dwyer ◽  
P Elson ◽  
N Simon ◽  
D Trump ◽  
...  
Keyword(s):  
Clinical Response ◽  
Response Rate ◽  
Residual Disease ◽  
Eastern Cooperative Oncology Group ◽  
Dose Intensity ◽  
Complete Response ◽  
Clinical Response Rate ◽  
Hematologic Toxicity ◽  
Survival Times ◽  
Moderate Nausea

Cyclophosphamide (CTX) 600 mg/m2, carboplatin 280 mg/m2, and cisplatin 50 mg/m2 were administered on day 1 every 4 weeks to 41 previously untreated ovarian cancer patients with residual disease greater than 2.0 cm after primary laparotomy. Of 22 patients with measurable disease treated with up to eight cycles of therapy, the overall clinical response rate was 73% (exact 95% confidence interval [CI], 50% to 89%), with 50% complete response (CR). Six of 11 clinical CR (cCR) patients underwent surgical restaging; three pathologic CRs (pCRs) and three pathologic partial responses (pPRs) with residual disease less than 2.0 cm were documented. Fourteen patients had nonmeasurable but assessable disease; the clinical response rate was 57% (Cl, 29% to 82%) with two (14%) CRs. Second-look surgery was performed in one of the two cCR patients; a pPR was documented. Five patients with nonassessable disease were stable during chemotherapy; two underwent surgery and had pCRs. The median time to treatment failure (TTF) was 14.8 months, and median survival for the 41 patients is 26.7 months. Overall, 37% of the patients had progression-free intervals of at least 2 years, and 27% have survival times in excess of 3 years. Hematologic toxicity was substantial but manageable, with 58% and 66% experiencing a granulocyte nadir less than 500/microL and a platelet nadir less than 50,000/microL, respectively. One treatment-associated fatality occurred as a result of leukopenic sepsis and renal failure in the setting of progressive disease and ureteral obstruction. Mild to moderate nausea and vomiting occurred in most patients, but none experienced severe ototoxicity or peripheral neuropathy. Over all courses, 73% of the projected dose intensity of CTX and carboplatin and 86% of cisplatin were delivered. Since granulocytopenia and thrombocytopenia were dose-limiting, the addition of colony-stimulating factors that support both myeloid and megakaryocyte precursors may permit further dose intensification.

Mucosal Biomarker of Innate Immune Activation Predicts Response to Vedolizumab in Crohn’s Disease

2019 ◽  
Author(s):  
Mark T Osterman ◽  
Ilyssa O Gordon ◽  
Elisabeth M Davis ◽  
Matthew Ciorba ◽  
Sarah C Glover ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Immune Activation ◽  
Clinical Remission ◽  
Response Rate ◽  
Intestinal Inflammation ◽  
Innate Immune ◽  
Clinical Response Rate ◽  
Innate Immune Activation

Abstract Objective Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn’s disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. Design Crohn’s disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn’s Disease (SES-CD). Results One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3–48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03–7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. Conclusions Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.

Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided cisplatin-based two-drug chemotherapy in unresectable non-small cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7118-7118
Author(s):  
Y. W. Moon ◽  
Y. T. Kim ◽  
J. H. Sohn ◽  
J. Chang ◽  
S. K. Kim ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Response ◽  
Response Rate ◽  
Predictive Accuracy ◽  
Clinical Response Rate ◽  
Chemotherapy Response ◽  
Chemosensitivity Test ◽  
Predictive Values ◽  
Platinum Sensitive ◽  
Response To Chemotherapy

7118 Background: Heterogeneity of tumor response to chemotherapy is a big obstacle in cancer treatment. The aim of this study was to investigate correlations of ATP-CRA and clinical outcome after ATP-TCA-guided cisplatin-based chemotherapy in unresectable NSCLC. Methods: From Sep. 2003 to Oct. 2005, ATP-CRA was done in tumor tissue specimen obtained from patients with suspected lung malignancy. ATP-CRA tested sensitivities of anticancer drugs used widely in advanced NSCLC such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabin, and vinorelbine. The cell death rate was determined by measuring the intracellular ATP levels of untreated controls and drug exposed cells. A sensitive drug was defined as a drug producing 30% or more reduction of ATP compared to untreated controls. Test-guided cisplatin-based two-drug chemotherapy was given to pathologically confirmed NSCLC. Results: 31 patients were enrolled and their median follow-up duration was 13.3 months. Response rate was 48.3%. Median progression-free and overall survivals were 4.4 months and 11.2 months, respectively. Patients were dichotomized into platinum-sensitive (S) and resistant (R) groups. S-group (19) contained cases sensitive to platinum alone (6) or both drugs (13). R-group (12) contained cases sensitive to none (9) or the other drug alone (3). Clinical response rate was higher in S-group (75.0% vs 35.3% in R-group; p = 0.0635). Considering correlations of test results and clinical response, positive/negative predictive values were 64.7% / 75.0% with the predictive accuracy of 69.0%. Although without significant differences in histology, stage, and performance status, S-group had longer progression-free (5.0 vs 2.4 months in R-group; p = 0.056) and overall (21.8 vs 9.7 months in R-group; p = 0.018) survivals. Conclusions: In vitro chemosensitivity test, ATP-CRA results and clinical outcome were correlated well after test-guided cisplatin-based two-drug chemotherapy in unresectable NSCLC, presenting favorable response and survival in platinum-sensitive versus resistant group. [Table: see text]

S-1 plus oxaliplatin compared with fluorouracil/leucovorin/oxaliplatin as neoadjuvant chemotherapy for locally advanced gastric carcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 147-147
Author(s):  
Jiren Yu ◽  
Yijun Wu ◽  
Yuan Gao ◽  
Qianyun Shen ◽  
Qing Zhang ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Gastric Carcinoma ◽  
Clinical Response ◽  
Response Rate ◽  
Locally Advanced ◽  
Preoperative Staging ◽  
Complete Response ◽  
Clinical Response Rate ◽  
R0 Resection ◽  
Advanced Gastric Carcinoma

147 Background: Perioperative chemotherapy could improve the prognosis compared with surgery alone. This study is to compare the efficacy and safety of S-1 and oxaliplatin (SOX) with fluorouracil, leucovorin and oxaliplatin (FOLFOX) as neoadjuvant chemotherapy for locally advanced gastric carcinoma. Methods: Patients with histologically confirmed locally advanced gastric carcinoma were enrolled and divided into two groups. Preoperative staging and response evaluation was achieved mainly by gastroscopy and abdominal computer tomography. Neoajuvant chemotherapy consisted of 2-6 cycles of S-1 80mg/m2 (2-week administration and 1-week rest) plus oxaliplatin 130mg/m2 on Day1 in SOX group, or 2 h infusion of 130mg/m2 oxaliplatin plus 2h infusion of 400 mg/m2 leucovorin, followed by infusion of 400 mg/m2 5-fluorouracil on Day 1 and 46 h 2.4 g/m2 bolus in FOLFOX group. The clinical response was evaluated after 2 cycles of chemotherapy, and surgery was attempted. Results: From 2009.9 to 2011.5, 88 patients were enrolled in this study(56 in SOX and 32 in FOLFOX). The clinical response rate was significant higher in the SOX compared with FOLFOX (54.7% vs. 31.2%, p=0.03). 68 patients received surgery(45 in SOX and 23 in FOLFOX), R0 resection rate was similar in both group (SOX: 93.3% vs. FOLFOX: 82.6%, p=0.22). Pathological complete response was observed in 3 patients in SOX group. All enrolled patients were evaluated for the adverse events (AE). The most common non-hematological AE was nausea (57.1% in SOX and 50% in FOLFOX) and vomiting (41.1% in SOX and 40.6% in FOLFOX). The major hematological AE included thrombocytopenia (37.5% in SOX and 21.9% in FOLFOX), neutropenia (33.9% in SOX and 53.1% in FOLFOX) and leukocytopenia (32.1% in SOX and 40.6% in FOLFOX). Conclusions: SOX had higher response rate and acceptable toxicity compared with FOLFOX as neoadjuvant chemotherapy.

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