A phase Ib/II clinical trial of a novel oxygen therapeutic in chemoradiation of glioblastoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2561-2561 ◽  
Author(s):  
Evan C. Unger ◽  
Jason D. Lickliter ◽  
Jeremy Ruben ◽  
Ross Jennens ◽  
Ganessan Kichenadasse ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Tumor Hypoxia ◽  
Standard Of Care ◽  
Supplemental Oxygen ◽  
Normal Brain ◽  
Before And After ◽  
Mri Scans ◽  
Dose Levels ◽  
Chemoradiation Treatment

2561 Background: Tumor hypoxia limits the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). Additionally, patient biomarkers are strong predictors of responsiveness to TMZ. The purpose of this study is to evaluate the use of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. Methods: 11 adult GBM patients have been enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) an hour prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) with supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To confirm tumor re-oxygenation, patients underwent TOLD MRI before and after DDFPe administration. Archived tumor specimens were studied with GliomaSTRAT assay for methylated genes predictive of response. Patients were also studied with serial MRI scans per standard of care and followed for survival. Results: There were minimal acute adverse events related to DDFPe administration. One patient at each of dose levels 0.1 and 0.17 mL/kg developed symptomatic radiation necrosis, which was judged to be related to DDFPe. Enrollment has continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. TOLD MRI showed significant decrease in T1of tumor tissue consistent with tumor re-oxygenation (p=0.015) with no significant change in oxygenation of normal brain tissue. Historically, the average overall survival for GBM patients, for both TMZ responders and non-responders, is about 14.6 months. The progress chart for patient overall survival is listed below, 4 patients have died. All other patients are alive. Conclusions: DDFPe is a promising oxygen therapeutic for reversing tumor hypoxia. A Phase II study is being planned to assess its effectiveness. Clinical trial information: NCT02189109. [Table: see text]

scholarly journals ACTR-18. A PHASE IB/II CLINICAL TRIAL OF DODECAFLUOROPENTANE EMULSION (DDFPE) AS A RADIOSENSITIZER IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi16-vi16 ◽  
Author(s):  
Jason Lickliter ◽  
Jeremy Ruben ◽  
Ross Jennens ◽  
Ganessan Kichenadasse ◽  
Cecelia Gzell ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Adverse Events ◽  
Tumor Hypoxia ◽  
Standard Of Care ◽  
Supplemental Oxygen ◽  
Tumor Oxygenation ◽  
Serious Adverse Events ◽  
Before And After ◽  
Mri Scans

Abstract BACKGROUND Tumor hypoxia decreases the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). The purpose of this study was to evaluate the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. METHODS With ethics approval and informed consent, 11 adult GBM patients were enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) within 5–30 minutes prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) while breathing supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To evaluate the reversal of tumor hypoxia, patients underwent oxygen-sensitive (TOLD) MRI before and after DDFPe administration. Patients were also studied with serial MRI scans per standard of care and followed for survival. RESULTS The non-serious adverse events considered by the investigator to be possibly, probably, or definitely related to DDFPe administration included fatigue (n=4), headache (n=2) and decrease in platelet count (n=2). Serious adverse events included two patients with symptomatic radiation necrosis: one patient at each of dose levels 0.1 and 0.17 mL/kg. Enrollment continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. Historically, the average overall survival for GBM patients is about 14.6 months. The median overall survival for the study was 591 days, or 19.4 months. According to independent review of the serial MR images, the median time to progression was 555 days, or 18 months, compared to a historical control of 6.9 months. TOLD MRI showed a trend in improved tumor oxygenation. CONCLUSION Although small, this trial shows that DDFPe used as a radiosensitizer appears to be safe and may provide some survival benefit. The FDA has allowed a Phase II clinical trial to assess its effectiveness.

scholarly journals Overall Survival As the Outcome for Randomized Clinical Trials With Effective Subsequent Therapies

2011 ◽  
Vol 29 (17) ◽  
pp. 2439-2442 ◽  
Author(s):  
Edward L. Korn ◽  
Boris Freidlin ◽  
Jeffrey S. Abrams
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Randomized Clinical Trial ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
Experimental Treatment ◽  
Standard Of Care ◽  
Current Standard ◽  
End Point

We review how overall survival (OS) comparisons should be interpreted with increasing availability of effective therapies that can be given subsequently to the treatment assigned in a randomized clinical trial (RCT). We examine in detail how effective subsequent therapies influence OS comparisons under varying conditions in RCTs. A subsequent therapy given after tumor progression (or relapse) in an RCT that works better in the standard arm than the experimental arm will lead to a smaller OS difference (possibly no difference) than one would see if the subsequent therapy was not available. Subsequent treatments that are equally effective in the treatment arms would not be expected to affect the absolute OS benefit of the experimental treatment but will make the relative improvement in OS smaller. In trials in which control arm patients cross over to the experimental treatment after their condition worsens, a smaller OS difference could be observed than one would see without cross-overs. In particular, use of cross-over designs in the first definitive evaluation of a new agent in a given disease compromises the ability to assess clinical benefit. In disease settings in which there is not an intermediate end point that directly measures clinical benefit, OS should be the primary end point of an RCT. The observed difference in OS should be considered the measure of clinical benefit to the patients, regardless of subsequent therapies, provided that the subsequent therapies used in both treatment arms follow the current standard of care.

Association of pre-existing autoimmune diseases in melanoma patients receiving immune checkpoint inhibition with improved survival and increased toxicity.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21586-e21586
Author(s):  
Nicholas Gulati ◽  
Arda Celen ◽  
Paul Johannet ◽  
Amelia Sawyers ◽  
Min Jae Kim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Immune Checkpoint ◽  
Standard Of Care ◽  
Controlled Clinical Trial ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Before And After ◽  
The Impact

e21586 Background: Immune checkpoint inhibition (ICI) improves progression-free (PFS) and overall survival (OS) for patients with metastatic melanoma (MM), but induces immune-related adverse events (irAEs). Pre-existing autoimmune disease (pre-AI) is considered a relative contraindication due to concerns of inciting autoimmune flare. We here tested the impact of pre-AI on both the survival and irAEs in MM patients treated with ICI. Methods: We examined MM patients treated with ICI who were enrolled in a clinicopathological database at NYULH with protocol-driven prospective follow up. We compiled a comprehensive list of 23 autoimmune diseases and examined the presence of these diseases prior to ICI treatment. We tested the associations between pre-AI and PFS, OS, and irAEs both in univariate and multivariate models. Results: 74/485 (15.3%) patients, who received 718 lines of ICI treatment as either standard of care or in clinical trials, had pre-AI, most commonly asthma (n=42), inflammatory bowel disease (n=9), psoriasis (n=9), rheumatoid arthritis (n=7), and eczema (n=6). In patients receiving ICI as standard of care (n=535), pre-AI was associated with irAEs (P=0.05) as well as with significantly improved PFS (P=0.024) and OS (P=0.007), controlling for patients’ sex, age, stage, ECOG status, and treatment line (1st line versus 2nd or 3rd line). However, no associations were observed between pre-AI and PFS (P=0.2) or irAEs (P=0.54) in the clinical trial group. Conclusions: Our data demonstrate the disparate impact of pre-AI on response and irAEs in standard of care versus the highly controlled clinical trial settings, and underscore the importance of examining the complex interaction between autoimmune disease before and after initiation of ICI. Our data also challenge the notion that clinicians should avoid use of ICI in pre-AI patients. More mechanistic research is needed to understand how to uncouple ICI response from toxicity.

Real world evidence: Abiraterone use post-docetaxel in metastatic castrate-resistant prostate cancer

2018 ◽  
Vol 25 (6) ◽  
pp. 1293-1300 ◽  
Author(s):  
Alisha Shivji ◽  
Raafi Ali ◽  
Scott North ◽  
Michael Sawyer ◽  
Sunita Ghosh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Real World ◽  
Performance Status ◽  
Retrospective Chart Review ◽  
Real World Evidence ◽  
Before And After ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Objectives The COU-AA-301 trial demonstrated that in men with metastatic castrate-resistant prostate cancer using abiraterone post-docetaxel increased overall survival. This study aims to assess this conclusion in a real world context. Design Retrospective chart review of a provincial Pharmacy BDM Database (a pharmacy dispensing software) and a provincial Electronic Chart (ARIA). Dispensing data, information on the state of the disease before and after abiraterone use, and information regarding effects of abiraterone were gathered. Setting Cancer centers in Alberta, Canada. Patients Metastatic castrate-resistant prostate cancer (CRPC) patients on abiraterone outside of a clinical trial who have previously had docetaxel chemotherapy for CRPC between February 2012 and May 2014. Primary outcome Overall survival from the time of abiraterone initiation. Results Overall survival increase of 17 months was consistent with the survival increase of 14.8 months observed in the pivotal trial. Conclusion Abiraterone is a valuable therapy post-docetaxel for metastatic CRPC, as in a real world context it demonstrated an increase in overall survival that was consistent with the findings of the clinical trial despite including a patient population of older age and lower performance status.

Effect of new dietary supplement on sperm quality

2012 ◽  
Vol 153 (45) ◽  
pp. 1787-1792 ◽  
Author(s):  
Mária Horváth ◽  
Endre Czeizel
Keyword(s):  
Adverse Effect ◽  
Clinical Trial ◽  
Dietary Supplement ◽  
Male Fertility ◽  
Sperm Quality ◽  
Sperm Count ◽  
Before And After ◽  
The Usa ◽  
New Treatments

Introduction: There is a decline in male fertility thus new treatments are needed. Aims: To test the efficacy of a new dietary supplement developed in the USA and registered as a curing drug in Hungary (OGYI). Methods: In a clinical trial 100 men with low sperm quality (spermium count 5–20 M/ml, good motility 10–40%, and adverse shape 30–50%) were examined. Results: Sperm parameters were measured before and after a 3-month treatment and after another 3-month without treatment. This dietary supplement statistically and clinically significantly improved sperm count and motility. In 74 cases this dietary supplement demonstrated a beneficial effect on sperm quality (more than 10% increase in sperm count, or quality of motility, or shape); in 16 cases the improvement exceeded 30%. No adverse effect could be accounted for this treatment. Conclusions: This new dietary supplement may contribute to the treatment of male infertility. Orv. Hetil., 2012, 153, 1787–1792.

Herbal Medicine for Glioblastoma: Current and Future Prospects

2020 ◽  
Vol 16 (8) ◽  
pp. 1022-1043
Author(s):  
Imran Khan ◽  
Sadaf Mahfooz ◽  
Mustafa A. Hatiboglu
Keyword(s):  
Cell Proliferation ◽  
Survival Rates ◽  
Standard Of Care ◽  
Natural Compounds ◽  
Treatment Modalities ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Cycle Regulation ◽  
Immense Potential

Background: Glioblastoma is one of the most aggressive and devastating tumours of the central nervous system with short survival time. Glioblastoma usually shows fast cell proliferation and invasion of normal brain tissue causing poor prognosis. The present standard of care in patients with glioblastoma includes surgery followed by radiotherapy and temozolomide (TMZ) based chemotherapy. Unfortunately, these approaches are not sufficient to lead a favorable prognosis and survival rates. As the current approaches do not provide a long-term benefit in those patients, new alternative treatments including natural compounds, have drawn attention. Due to their natural origin, they are associated with minimum cellular toxicity towards normal cells and it has become one of the most attractive approaches to treat tumours by natural compounds or phytochemicals. Objective: In the present review, the role of natural compounds or phytochemicals in the treatment of glioblastoma describing their efficacy on various aspects of glioblastoma pathophysiology such as cell proliferation, apoptosis, cell cycle regulation, cellular signaling pathways, chemoresistance and their role in combinatorial therapeutic approaches was described. Methods: Peer-reviewed literature was extracted using Pubmed, EMBASE Ovid and Google Scholar to be reviewed in the present article. Conclusion: Preclinical data available in the literature suggest that phytochemicals hold immense potential to be translated into treatment modalities. However, further clinical studies with conclusive results are required to implement phytochemicals in treatment modalities.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

scholarly journals AEROBIC EXERCISE VOLUME, NOT PRESCRIPTION, INFLUENCES POST-CONCUSSION SYMPTOMS: A RANDOMIZED CLINICAL TRIAL

2021 ◽  
Vol 9 (7_suppl3) ◽  
pp. 2325967121S0014
Author(s):  
David R. Howell ◽  
Danielle Hunt ◽  
Stacey E. Aaron ◽  
William P. Meehan ◽  
Can Ozan Tan
Keyword(s):  
Clinical Trial ◽  
Aerobic Exercise ◽  
Symptom Severity ◽  
Exercise Prescription ◽  
Standard Of Care ◽  
Care Group ◽  
Initial Symptom ◽  
Initial Visit ◽  
Severity Scores ◽  
Text Figure

Background: Current recommendations for sport-related concussion uniformly emphasize the importance of physical activity. However, specifics of this recommendation remain vague and do not account for an exercise dosage or compliance. Purposes: First, we examined if an 8-week individualized sub-symptom threshold aerobic exercise prescription, initiated within the first two weeks of concussion, alleviates symptom severity or affects the amount of exercise performed during the study. Second, we examined whether prescription adherence, rather than randomized group assignment, reflects the actual impact of aerobic exercise in post-concussion recovery. Methods: For this single-site prospective randomized clinical trial, participants completed an aerobic exercise test within 14 days of injury, and were randomized to an individualized aerobic exercise program or standard-of-care, and returned for assessments 1 month and 2 months after the initial visit (Table 1). The aerobic exercise group was instructed to exercise 5 days/week, 20 minutes/day, at a target heart rate based on an exercise test at the initial visit. Participants reported their symptom exercise volume each week over the 8-week study period, and reported symptoms at each study visit (initial, 1 month, 2 month). Results: Initial symptom severity was not different between randomized groups (Figure 1A), and no significant differences in symptom severity were found at the 4-week (Figure 1B) or 8-week (Figure 1C) assessment. In addition, there was no significant differences between groups for average weekly exercise volume during the first four weeks (Figure 2A) or second four weeks (Figure 2B) of the study. During the first four weeks of the study, 65% (n=11/17) of the exercise intervention participants were compliant with their exercise recommendation (≥100 min/week), compared to 45% (n=9/20) of the standard-of-care group (p=0.33). During the second four weeks of the study, 71% (n=12/17) of the exercise prescription group exercised ≥100 min/week, compared to 55% (n=11/20) of the standard-of-care group (p=0.50). When grouped by exercise volume, the group who exercised ≥100 minutes/week during the first month of the study reported significantly lower symptom severity scores than those who exercised <100 minutes/week (Figure 3B), despite similar initial symptom severity scores (Figure 3A). Conclusion: Participant randomization within 14 days of concussion did not lead to a significant reduction in symptoms, or greater exercise volume. Given that greater exercise volume was associated with lower symptoms after one month of the study, researchers and clinicians should pay particular attention to adherence to aerobic exercise programs for the treatment of concussion. [Table: see text][Figure: see text][Figure: see text][Figure: see text]

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