A phase III, randomized, controlled, superiority trial evaluating the fibrin pad versus standard of care in controlling parenchymal bleeding during elective hepatic surgery

Abstract Background Acute chest syndrome (ACS) is the leading cause of mortality in sickle cell disease (SCD). The pathogenesis of ACS is complex and not entirely understood with multiple etiologies likely contributing simultaneously. One particular etiology is pulmonary vascular occlusion due to thrombosis. Thus, anticoagulation is an attractive therapeutic modality. Methods This was a single-center, randomized controlled, open-label, pilot study to determine the feasibility of performing a larger multicenter phase III trial to assess the effects of unfractionated heparin (UFH) in ACS. Subjects were randomized within 24 h of diagnosis of ACS to one of two treatment arms, UFH, and standard of care (SOC), or no UFH and SOC. UFH was given intravenously for 7 days, or until discharge, if discharge was shorter than 7 days. SOC consisted of intravenous fluids, antibiotics, supplemental oxygen, analgesia, red blood cell transfusion, and exchange transfusion. Results From July 2014 to June 2018, a total of 7 patients underwent randomization (four patients received UFH in addition to SOC and 3 patients received SOC only). Two of the prespecified feasibility criteria were not met: the capacity to consent eligible individuals and the timely notification of hospitalized patients with ACS necessary to permit randomization within 24 h of diagnosis; thus, as a result of poor enrollment, the study was terminated early. The duration of hospitalization was 279.43 (SD 267.98) and 127.31 (SD 137.70) h in the UFH and SOC arms, respectively. The duration of hypoxemia, leukocytosis, fever, and moderate to severe pain was 117.52 (SD 60.52), 24.90 (SD 29.69), 117.52 (SD 60.52), and 117.52 (SD 60.52) h, respectively, in the UFH group, and 51.49 (SD 44.79), 0, 53.11 (SD 25.06), and 88.68 (SD 72.77) h, respectively, in the SOC group. No major bleeding was noted in either group. Conclusions Our study did not achieve prespecified feasibility criteria, resulting in poor enrollment and early termination, and serves to highlight some of the pitfalls experienced in clinical research in SCD. It did show the use of UFH without any major adverse events in 7 subjects. No future large-scale study is planned. Trials registration Registered at ClinicalTrials.gov (NCT #02098993) on March 28, 2014.

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Clinical Equipoise for Trials of Novel Biologic Therapies, Therapeutic Success Rates, and Predictors of Success: A Meta-Analysis

JCO Precision Oncology ◽

10.1200/po.17.00062 ◽

2017 ◽

pp. 1-12

Author(s):

Doah Cho ◽

Felicia T. Roncolato ◽

Johnathan Man ◽

John Simes ◽

Sarah J. Lord ◽

...

Keyword(s):

Meta Analysis ◽

Progression Free Survival ◽

Standard Of Care ◽

Phase Iii ◽

Predictors Of Success ◽

Biologic Therapies ◽

Therapeutic Success ◽

Free Survival ◽

Randomized Controlled ◽

Phase Iii Trials

Purpose The demand for more rapid access to novel biologic therapies than randomized controlled trials can deliver is a topic of ongoing study and debate. We aimed to inform this debate by estimating therapeutic success from phase III trials comparing novel biologic therapies with standard of care and identifying predictors of success. Methods This was a meta-analysis of phase III trials evaluating novel biologic therapies in advanced breast, colorectal, lung, and prostate cancers. Therapeutic success was defined as statistically significant results for the primary end point favoring novel biologic therapies. Results Of 119 included phase III trials (76,726 patients), therapeutic success was 41%, with a statistically significant relative reduction in disease progression and death for novel biologic therapies over standard of care of 20% and 8%. Therapeutic success did not improve over time (pre-2010, 33%; 2010 to 2014, 44%; P = .2). Predictors of success were a biomarker-selected population (odds ratio, 4.74; 95% CI, 2.05 to 10.95) and progression-free survival end point compared with overall survival (odds ratio, 5.22; 95% CI, 2.41 to 11.39). Phase III trials with a biomarker-selected population showed a larger 28% progression-free survival benefit than phase III trials overall (hazard ratio, 0.72; 95% CI, 0.70 to 0.75) but similar 8% overall survival benefit (hazard ratio, 0.92; 95% CI, 0.90 to 0.94). Therapeutic success of phase III trials with and without a preceding phase II trial were 43% and 30%, respectively Conclusion Therapeutic success of novel biologic therapies in phase III trials, including therapies with a matching predictive biomarker, was modest and has not significantly improved over time. Equipoise remains and supports the ongoing ethical and scientific requirement for phase III randomized controlled trials to estimate treatment efficacy and assess the value of potential biomarkers.

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Safety and Hemostatic Effectiveness of the Fibrin Pad for Severe Soft-Tissue Bleeding During Abdominal, Retroperitoneal, Pelvic, and Thoracic (Non-cardiac) Surgery: A Randomized, Controlled, Superiority Trial

World Journal of Surgery ◽

10.1007/s00268-015-3106-5 ◽

2015 ◽

Vol 39 (11) ◽

pp. 2663-2669 ◽

Cited By ~ 8

Author(s):

Jonathan Koea ◽

Peter Baldwin ◽

Jessica Shen ◽

B. Patel ◽

Jonathan Batiller ◽

...

Keyword(s):

Cardiac Surgery ◽

Soft Tissue ◽

Randomized Controlled ◽

Superiority Trial ◽

Severe Soft Tissue ◽

Fibrin Pad

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Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.18_suppl.lba4 ◽

2016 ◽

Vol 34 (18_suppl) ◽

pp. LBA4-LBA4 ◽

Cited By ~ 9

Author(s):

Antonio Palumbo ◽

Asher Alban Akmal Chanan-Khan ◽

Katja Weisel ◽

Ajay K. Nooka ◽

Tamas Masszi ◽

...

Keyword(s):

Safety Profile ◽

Sensory Neuropathy ◽

Standard Of Care ◽

Phase Iii ◽

Randomized Controlled Study ◽

Controlled Study ◽

Prior Therapy ◽

Randomized Controlled ◽

Grade 3 ◽

Line Of Therapy

LBA4 Background: Daratumumab (D), a human anti-CD38 IgGκ mAb, induces deep and durable responses with a favorable safety profile in RRMM pts. We report a pre-specified interim analysis of the first randomized controlled study of D (CASTOR; NCT02136134). Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of bortezomib (V)/dexamethasone (d) (V: 1.3 mg/m2sc on Days 1, 4, 8, 11; d: 20 mg po on Days 1, 2, 4, 5, 8, 9, 11, 12) ± D (16 mg/kg iv qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Primary endpoint was PFS. Results: 498 pts (DVd, 251; Vd, 247) were randomized. Baseline demographics and disease characteristics were well balanced. Pts received a median of 2 prior lines of therapy (range 1-10). 66% received prior V; 76% received prior IMiD; 48% received prior PI and IMiD; 33% were IMiD-refractory; 32% were refractory to last line of prior therapy. With median follow-up of 7.4 months, D significantly improved median PFS (61% reduction in risk of progression) and TTP for DVd vs Vd (Table). D significantly increased ORR (83% vs 63%, P <0.0001), and doubled rates of ≥VGPR (59% vs 29%, P <0.0001), and ≥CR (19% vs 9%, P= 0.0012) for DVd vs Vd, respectively; median duration of response was NR vs 7.9 months, respectively. Most common (>25%) AEs (DVd/Vd) were thrombocytopenia (59%/44%), peripheral sensory neuropathy (47%/ 38%), diarrhea (32%/22%) and anemia (26%/31%). Most common grade 3/4 AEs (>10%) were thrombocytopenia (45%/33%), anemia (14%/16%), neutropenia (13%/4%). 7%/9% of pts discontinued due to a TEAE. D-associated infusion-related reactions (45% of pts) mostly occurred during the first infusion; most were grade 1/2 (grade 3/4, 9%/0%). Conclusions: D significantly improved PFS, TTP, and ORR in combination with Vd vs Vd alone. DVd doubled both VGPR and sCR/CR rates vs Vd alone. Safety of DVd is consistent with the known safety profile of D and Vd. The addition of D to Vd should be considered a new standard of care for RRMM pts currently receiving Vd alone. Clinical trial information: NCT02136134. [Table: see text]

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Evaluation of Early and Late Toxicities in Chemoradiation Trials

Journal of Clinical Oncology ◽

10.1200/jco.2007.13.3983 ◽

2007 ◽

Vol 25 (26) ◽

pp. 4096-4103 ◽

Cited By ~ 120

Author(s):

Søren M. Bentzen ◽

Andrea Trotti

Keyword(s):

Adverse Effects ◽

Tissue Injury ◽

Late Toxicity ◽

Standard Of Care ◽

Phase Iii ◽

Serious Adverse Events ◽

Randomized Controlled ◽

Solid Malignancies ◽

Phase Iii Trials ◽

Low Incidence

Combined chemoradiotherapy is increasingly becoming a standard of care for the nonoperative management of a variety of solid malignancies. A string of randomized controlled phase III trials have shown statistically significant and clinically relevant improvements in outcome, ostensibly without any apparent increase in late toxicity. However, the reliability and the sensitivity of toxicity reporting in most trials are questionable. Audits and phase IV studies suggest that the chemoradiotherapy success comes at a price in terms of late toxicity. This review presents some of the challenges in recording, analyzing, and reporting toxicity data. Methods for summarizing toxicity are reviewed, and a new investigational metric, the TAME reporting system, is discussed. The need for special vigilance in the era of molecular-targeted agents is emphasized because of the possibility that unexpected serious adverse events with a low incidence may occur. Finally, we discuss how progress in molecular pathology and radiation biology may provide novel opportunities for stratifying patients according to risk of adverse effects, interventional targets for reducing or treating adverse effects, and surrogate markers of normal-tissue injury.

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