Multiple-objective response-adaptive repeated measurement designs in clinical trials for binary responses

2013 ◽  
Vol 33 (4) ◽  
pp. 607-617 ◽  
Author(s):  
Yuanyuan Liang ◽  
Yin Li ◽  
Jing Wang ◽  
Keumhee C. Carriere
Keyword(s):  
Clinical Trials ◽  
Objective Response ◽  
Repeated Measurement ◽  
Multiple Objective ◽  
Binary Responses

Crizotinib Versus Chemotherapy on ALK-positive NSCLC: A Systematic Review of Efficacy and Safety

2018 ◽  
Vol 19 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Mingxia Wang ◽  
Guanqi Wang ◽  
Haiyan Ma ◽  
Baoen Shan
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Events ◽  
Objective Response Rate ◽  
Retrospective Studies ◽  
Response Rate ◽  
Objective Response ◽  
Treated Group ◽  
Efficacy And Safety ◽  
Alk Positive

Introduction: Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. </P><P> Methods: We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). Results: Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity. This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations.

EPID-24. TRANSCRIPT: A cenTRAl NERVOUS SYSTEM CANCER CLINICAL tRIals PostmorTem

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi91-vi91
Author(s):  
Yeonju Kim ◽  
Terri Armstrong ◽  
Mark Gilbert ◽  
Orieta Celiku
Keyword(s):  
Central Nervous System ◽  
Overall Survival ◽  
Clinical Trials ◽  
Nervous System ◽  
Brain Tumor ◽  
Objective Response ◽  
Survival Rates ◽  
Maximum Tolerated Dose ◽  
Secondary Outcome ◽  
Patient Reported

Abstract BACKGROUND Despite the growing number of neuro-oncology clinical trials, there have been limited advances in the treatment of malignant primary central nervous system tumors. We surveyed the landscape of past, ongoing, and planned trials to assess trends in their interventions, outcomes, and design considerations to guide future studies. METHODS Data on interventional trials on ClinicalTrials.gov were accessed programmatically using AACT and R. Neuro-oncology trials were isolated using primary malignant brain tumor classification terms. Instrument names from PROQOLID were used to identify clinical outcome assessment (COA) use. Linear regression was used to assess chronological trends; power analyses utilized CBTRUS survival rates among trials investigating overall survival. RESULTS We identified 3039 interventional brain tumor trials that started between 1966 and 2025. Trials were most frequently phase II (43%), completed (40%), non-blinded (92%), single-group assignment (65%), non-randomized (51%) studies targeting glioblastoma (45%). Planned outcomes were reported by 93% of trials; this included adverse event or toxicity (54%), overall/x-year survival (44%), progression free survival (43%), maximum tolerated dose (16%), and objective response rate (14%). Evaluating the anticipated and actual trial enrollment, we estimate that only 10% and 8% of trial arms, respectively, were sufficiently powered to assess overall survival endpoints. 21% of trials mentioned the use of a COA (first trial initiated in 1992), majority of which were patient-reported outcomes. Among these, 25% and 58% reported COA as a primary or secondary outcome, respectively. The rate of COA use increased linearly over time at 1.1%/year but remained less than 5 trials per year until 2003. Ongoing work is investigating treatment mechanisms of actions and evidence of preclinical efficacy among brain tumor studies. CONCLUSIONS Low randomization rates and underpowered trial design may impede interpretability of efficacy. Increasing trends in COA use suggests cumulative influence of advocacy efforts to holistically evaluate net clinical benefit of interventions.

scholarly journals Indicadores (Outcomes) Primários e Secundários em Ensaios Clínicos Oncológicos: Definição e Usos

2014 ◽  
Vol 27 (4) ◽  
pp. 498
Author(s):  
António Vaz-Carneiro ◽  
Ricardo Da Luz ◽  
Margarida Borges ◽  
João Costa
Keyword(s):  
Clinical Trials ◽  
Methodological Issue ◽  
Objective Response ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Free Survival ◽  
Patient Reported ◽  
Oncology Clinical Trials ◽  
Alternative Drug ◽  
Selection Of

<strong>Introduction:</strong> The proof of efficacy from a therapeutic intervention in oncology must be defined through well conducted clinical trials. One of the most important methodological issue is the outcome selection needed to calculate measures of association allowing definition of clinical efficacy.<br /><strong>Material and Methods:</strong> We designed a narrative revision based on some of the international regulatory instructions from drug agencies, as well as consensus papers from scientific oncology societies, listing and critically assessing each outcome used in oncology clinical trials.<br /><strong>Results:</strong> We identified as being the most important outcomes in oncology trials the overall survival, the progression free survival/ disease-free survival, the toxicity, the quality of life/patient- reported outcomes and the objective response rate.<br /><strong>Discussion:</strong> The selection of the primary outcome must be based on therapeutic efficacy as well as toxicity, expected survival, alternative drug regimens and even disease prevalence.<br /><strong>Conclusion:</strong> The selection of efficacy outcomes for clinical trials in oncology is very important and its selection must be well justified, and depends on the type of disease, the patients and the drug being studied.<br /><strong>Keywords:</strong> Clinical Trials as Topic; Neoplasms; Medical Oncology; Treatment Outcome.

scholarly journals Analysis of repeated measurement data in the clinical trials

2013 ◽  
Vol 4 (2) ◽  
pp. 77 ◽  
Author(s):  
RakeshKumar Rana ◽  
Richa Singhal ◽  
Vineeta Singh
Keyword(s):  
Clinical Trials ◽  
Measurement Data ◽  
Repeated Measurement

scholarly journals Efficacy of Chemotherapy or Chemo-Anti-PD-1 Combination after Unsatisfactory Response of Anti-PD-1 Therapy for Relapsed and Refractory Hodgkin Lymphoma: A Retrospective Series from Lysa Centers

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 652-652
Author(s):  
Cédric Rossi ◽  
Julia Gilhodes ◽  
Marie Maerevoet ◽  
Charles Herbaux ◽  
Pauline Brice ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Complete Response ◽  
High Rate ◽  
High Dose ◽  
Group 2 ◽  
Group 1

Abstract Introduction: Hodgkin lymphoma (HL) pts who relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV) therapy have a poor outcome. For these relapsed and refractory (R/R) HL pts, anti-PD-1 therapy gives a high rate of objective responses. However, the rate of complete response (CR) remains modest and in the updated results of anti-PD-1 therapy clinical trials, about 50% of pts are still without progressive disease after one year of treatment. As anti-PD-1 therapy modifies the anticancer immune response, we hypothesize that anti-PD-1 therapy may increase sensitivity to chemotherapy (CT) given after anti-PD-1 therapy (sequential strategy) or in combination with anti-PD-1 therapy after an unsatisfactory response to immunotherapy (concomitant strategy). We retrospectively analyzed these two clinical situations in 30 R/R HL pts from LYSA centers treated with anti-PD-1 therapy. Methods: We included R/R HL pts from 14 LYSA centers who received anti-PD-1 therapy in the context of clinical trials (N=4) or an authorization for temporary use (ATU) from the French medical drug agency (N=26). Before the anti-PD-1 therapy, pts had received a median of six (range, 2-14) lines of therapy, 69% had HDT+ASCT, 14% had allograft and 93% had been treated with BV. We considered two groups of pts: i. 19 pts (63%) in whom the anti-PD-1 therapy was stopped at the introduction of CT (Group 1); ii. 11 pts (37%) with an unsatisfactory response to anti-PD-1 therapy in whom a combination of CT with immunotherapy was initiated to optimize the response (Group 2). The quality of the response after the introduction of CT was evaluated retrospectively by each treating physicians according to Cheson 2007 or 2014 criteria. We also determined whether new CT treatments after and in combination with anti-PD-1 therapy led to unexpected toxicities and whether new treatment schedules made pts eligible for allograft. Results: At the start of anti-PD-1, the median age of pts was 37 years old (range, 20-75), 24% had Ann Arbor III/IV stages, 34% had B symptoms and 21% had a performance status (PS) of 2-3. Patients received a median of 10 infusions (range, 2-52) of anti-PD-1 therapy with nivolumab (N=26, 87%) or pembrolizumab (N=4, 13%). The best responses achieved during anti-PD-1 therapy were a complete response (CR) for 5 patients, a partial response (PR) for 17 pts, stable disease (SD) for 2 pts and progression for 6 pts. In group 1, 17 pts were in progression, one pt in PR, and another pt in SD at the end of anti-PD-1 therapy alone. In group 1, after anti-PD-1 therapy, the pts were treated with vinblastine (N=3), gemcitabine (N=2) or bendamustine alone (N=3) or in combination with BV (N=4), GVD (N=1), ICE (N=1), DHAP (N=1), escalated BEACOPP (N=1), vinorelbine (N=1), vepeside (N=1) and caelyx (N=1). In group 2, before the combination, the response status was progression for 7 pts and PR for 4 pts. In group 2, to optimize the response to anti-PD-1, pts received vinblastine (N=7), gemcitabine (N=2) and BV (N=2). In the 28 evaluable pts, 11/18 (61%) in group 1 and 9/10 (90%) in group 2 showed an improved response after chemotherapy alone or combination with anti-PD-1 therapy respectively. In group 1, there were 6 CR (32%), 5 PR (26%), 1 SD (5%) and 6 PD (32%) (Figure 1B). In group 2, there were 5 CR (45%), 5 PR (45%) and 1 SD (10%) (Figure 1A). Of note, among the ten pts treated with vinblastine, 4 were in CR, 3 in RP, 1 in SD and 2 in progression. No unexpected toxicity was observed during the CT. Four pts had an allograft after the sequential CT (N=3) and concomitant CT strategy (N=1). Three pts were in CR 274, 279 and 480 days after the allograft and the fourth has not yet been evaluated. Allografts are now scheduled for 6 pts. With a median follow-up of 9.1 months (95%CI, 6.1-14) following the initiation of chemotherapy (alone or combined) the median PFS and OS were 8.4 and 14.6 months, respectively. Conclusions: Our retrospective study showed that pts with an unsatisfactory response or PD with anti-PD-1 therapy had a new objective response with CT alone (61%) or CT in combination with anti-PD-1 therapy (90%). This response could make some pts eligible for allograft. Prospective clinical trials are needed to confirm the synergistic effect of CT with anti-PD-1 therapy and to determine which CT provides the best results in combination with these checkpoint inhibitors. Figure 1 Figure 1. Disclosures Ysebaert: Janssen: Consultancy, Research Funding, Speakers Bureau. Ghesquières: Celgene and Mundipharma: Consultancy, Honoraria; Roche: Research Funding.

Efficacy of targeted therapy in alveolar soft part sarcoma: A systematic review and meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e23543-e23543
Author(s):  
Na Hyun Kim ◽  
Chenyu Sun ◽  
Apurwa Prasad ◽  
Humaed Mohammed Abdul ◽  
Saba Batool ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Disease Control ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Soft Part ◽  
Objective Response ◽  
Chromosome 17 ◽  
Alveolar Soft Part Sarcoma

e23543 Background: Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma, characterized by a specific unbalanced translocation leading to the fusion of the TFE3 gene on chromosome-X to the ASPSCR1 gene on chromosome-17. Despite its indolent course, ASPS presents a challenge in treatment due to its resistance to conventional anthracycline-based chemotherapy and lack of large scale trial data for this rare sarcoma. This review aimed to assess the efficacy of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) in metastatic alveolar soft part sarcoma. Methods: A systematic search was performed on Embase and Medline databases for studies that assessed best response of patients with unresectable or metastatic ASPS to TKI and ICI therapy, according to the Response Evaluation Criteria in Solid Tumors (RECIST) edition 1.0 or 1.1. This study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol. Four independent reviewers screened abstracts and extracted the data; any discrepancy was resolved by discussion among reviewers. Pooled objective response rate (ORR) and disease control rate (DCR) were obtained using the Freeman-Tukey double-arcsine transformation using random effects model on STATA software (version. 16.1, StataCorp). Results: 27 articles and abstracts published between 2011 and 2020 were included in the review, resulting in 2 randomized clinical trials (104 participants), 14 single arm prospective trials (214 participants), and 11 retrospective studies (120 patients). Among clinical trials, the pooled ORR and DCR were 18% (95% confidence interval [CI] 8 - 30%; I2 = 72.25%; p < 0.01) and 87% (95% CI 97 - 93%; I2 = 43.2%; p = 0.03) respectively. Conclusions: The response rate to targeted therapy in metastatic ASPS is not only clinically meaningful, but also comparable to that of first-line chemotherapy. The majority of patients receiving targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated response to other agents. More randomized trials are warranted to expand treatment options and compare to standard of care regimens.

Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and low Karnofsky performance status: Results from the CheckMate 920 trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 315-315
Author(s):  
Thomas E. Hutson ◽  
Bradley Curtis Carthon ◽  
Jeffrey Yorio ◽  
Sunil Babu ◽  
Heidi Ann McKean ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Clear Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Safety And Efficacy ◽  
Grade 3

315 Background: Combination therapy with nivolumab + ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability for patients (pts) with previously untreated advanced renal cell carcinoma (aRCC). Most pivotal clinical trials in pts with aRCC have excluded pts with low Karnofsky performance status (KPS; < 70%). CheckMate 920 is a multi-arm, phase IIIb/IV, open-label clinical trial of NIVO+IPI treatment in pts enrolled in a community practice setting with aRCC and a high unmet medical need. We present safety and efficacy results for the cohort of pts with aRCC of any histology and KPS 50%–60% from CheckMate 920 (NCT02982954). Methods: Pts with previously untreated advanced/metastatic RCC and KPS 50%–60% received NIVO 3 mg/kg + IPI 1 mg/kg Q3W × 4 doses followed by 480 mg NIVO Q4W for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 25 treated pts with KPS 50%–60%, 76% were men; median age was 67 years (range, 34–81). IMDC risk was favorable in 0%, intermediate in 32%, and poor in 68% of pts; 84% had clear cell and 16% had non-clear cell RCC histology. With a minimum follow-up of 25 months, median duration of therapy (95% CI) was 2.3 months (2.1–7.7) for NIVO and 2.1 months (2.1–2.1) for IPI. The median number of doses (range) received was 4 (1–27) for NIVO and 4 (1–4) for IPI; 76% of pts received ≥ 4 NIVO doses and 68% received all 4 IPI doses. The only grade 3–4 imAEs by category were hepatitis (4.0%) and adrenal insufficiency (4.0%). No grade 5 imAEs occurred. Overall, 4 (16%) pts discontinued due to any-grade adverse events (n = 1 each for elevated AST, malignant neoplasm progression, back pain, and acetabulum fracture). Of 18 evaluable pts, ORR was 33.3% (95% CI, 13.3–59.0); no pts had a complete response and 6 had partial response. Median time to objective response was 4.5 months (range, 2.5–24.7). Median duration of objective response was 20.6 months (range, 0.03+–24.2+). Median PFS was 4.6 months (95% CI, 2.5–14.8). Median OS was 15.6 months (95% CI, 5.3–25.1). Conclusions: NIVO+IPI demonstrated an acceptable safety profile and promising antitumor activity in pts with previously untreated aRCC and KPS 50%–60%. The combination was tolerated at a dose intensity similar to that observed in clinical trials conducted in pts with higher KPS (≥ 70%). These data support the value of NIVO+IPI in pts who may not be considered ideal candidates for this therapy and consequently may have limited treatment options. Clinical trial information: NCT02982954 .

Management of salivary gland malignancies: current and developing therapies

2011 ◽  
Vol 2 (2) ◽  
pp. 86 ◽  
Author(s):  
Mark Agulnik ◽  
Camille F. McGann ◽  
Bharat B. Mittal ◽  
Sara C. Gordon ◽  
Joel B. Epstein
Keyword(s):  
Clinical Trials ◽  
Salivary Gland ◽  
Treatment Guidelines ◽  
Objective Response ◽  
Response Rates ◽  
Cytotoxic Agents ◽  
Disease Response ◽  
Phase Ii Studies ◽  
Duration Of Response ◽  
New Treatment

Salivary gland tumors are rare, clinically diverse neoplasms that represent less than 1% of all malignancies. In locoregional recurrent or metastatic disease, systemic therapy is the standard approach. While numerous small phase II studies have evaluated the activity of cytotoxic agents, either alone or in combination, the response rates are generally modest with objective response rates ranging from 15%–50%. Duration of response is cited in the range of 6–9 months. Given this, further evaluation of novel therapies is mandatory in these diseases. With the emergence of molecular targeted therapy, these tumors become optimal candidates for trials of investigational drugs and established drugs for new indications. Of note, given the often indolent nature of disease, only patients with progressive disease should be enrolled and treated on these clinical trials. Study designs must incorporate stringent inclusion criteria to enable accurate reporting of disease response and stabilization. With dedication and co-operation, patients with these rare neoplasms can be accrued to clinical trials and the establishment of new treatment guidelines will be forthcoming.

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