Prospective manipulation of the gut microbiome with Microbial Ecosystem Therapeutic 4 (MET4) in locoregionally advanced oropharyngeal squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation (ROMA2).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6059-6059
Author(s):  
Geoffrey Alan Watson ◽  
Alya Heirali ◽  
Marc Oliva Bernal ◽  
Kyla Cochrane ◽  
Emma Allen-Vercoe ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gut Microbiome ◽  
Clinical Trial Design ◽  
Alpha Diversity ◽  
Standard Of Care ◽  
Ecological Effect ◽  
Stage Iii ◽  
Fecal Transplant ◽  
Ecological Changes ◽  
Stool Samples

6059 Background: Therapeutic manipulation of the gut microbiome in cancer patients (pts) is an area of active investigation. MET4 (NuBiyota) is an oral alternative to fecal transplant consisting of a mixture of human gut bacteria associated with immunotherapy (IO) response. We previously reported variation in IO-responsive taxa across stages in human papilloma virus related (HPV+) LA-OPSCC pts treated with chemoradiotherapy (CRT) (Oliva et al., ASCO 2020). ROMA-2 is the first interventional study evaluating the safety, feasibility and ecological effect of MET4, in combination with definitive CRT in HPV+ LA-OPSCC (NCT03838601). Methods: This is an investigator-initiated study of pts with HPV+ LA-OPSCC treated with standard of care CRT. MET4 is administered daily until week 4 of CRT or unacceptable toxicity. Stool samples are collected at baseline, week 4, week 8-10, and 2-months post CRT. Bacterial V4 16S rDNA was extracted from stool and sequenced. Microbiome analyses were conducted in R using DADA2, phyloseq and DESeq2. Results: As of February 11 2021, 25 pts have been enrolled. A total of 50 stool samples from the first 14 pts were collected (98% adherence) and analyzed. Baseline cohort characteristics: median age = 62.5 (range, 48-69); Stage I/II/III = 5/1/8; use of antibiotics = 1pt. 3 pts did not complete the 3-week course of MET4 treatment due to non-compliance (n = 1), withdrawal of consent (n = 1) and grade 2 diarrhea (n = 1). Other reported MET4-related adverse events (all grade 1) included bloating (n = 2), flatulence (n = 1) and belching (n = 1). No longitudinal changes in alpha-diversity were seen from baseline through follow up. Administration of MET4 resulted in a transient trend towards increased cumulative MET4 taxa relative abundance (RA) by week 4. Stage III patients demonstrated the lowest MET4 taxa RA at baseline, and the greatest increase in MET4 taxa RA from baseline to week 4. By week 4 the following taxa in all pts were increased compared to baseline: Eubacterium hallii (21.71 Log2Fold change[L2FC], padj < 0.001) and Parabacteroides johnsonii (23.67 L2FC, padj < 0.001). An increase in the following taxa was observed by weeks 8-10 compared to baseline: Akkermansia muciniphilla (3.75 L2FC, padj = 0.027), Bacteroides fragilis (6.73 L2FC, padj = 0.010), Alistipes onderdonkii (3.30 L2FC, padj = 0.049) and Parabacteroides distasonis (24.43 L2FC, padj < 0.001). Conclusions: Manipulation of the gut microbiota in these pts was feasible and safe. MET4-induced ecological changes are heterogenous and vary by taxa. MET4 taxa implicated in IO-response were increased by week 4 and week 8-10. This increase was higher in pts with stage III disease. These data suggest that specific subgroups may benefit from combination IO therapy and may guide pt selection for further interventional clinical trial design. Clinical trial information: NCT03838601.

scholarly journals Mutational analysis of >14,000 NGS tests from community oncology practices: The Sarah Cannon molecular landscape.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 26-26
Author(s):  
Howard A. Burris III ◽  
Daniel Schlauch ◽  
Yasha Sharma ◽  
Shaita Picard ◽  
Connor Higgins ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mutational Analysis ◽  
Clinical Trial Design ◽  
Standard Of Care ◽  
Clinical Decision ◽  
Data Infrastructure ◽  
It Systems ◽  
Community Oncology ◽  
Real World Evidence ◽  
Molecular Landscape

26 Background: Utilization of NGS-based testing for patients in community oncology settings continues to grow. A comprehensive analysis of the molecular landscape of > 14,000 patients with commercial tissue-based and plasma-based NGS (tbNGS and pbNGS) testing from Sarah Cannon’s (SC) network of community oncologists between 2012 and 2018 was performed. These data aid clinical trial design/feasibility and identify rare and actionable mutations in the community oncology setting. Methods: Medical Oncologists in the SC network ordered NGS-based molecular profiling for their patients as standard of care. Data from multiple commercial vendors starting in 2012 were harmonized and analyzed. Results: On average, tbNGS (n = 8938) and pbNGS (n = 5419) tests revealed 14 and 4 mutations/sample, respectively. The top 10 mutated genes from both tbNGS and pbNGS - tests are in the table. The most predominant mutation-types detected were SNVs in both tbNGS and pbNGS tests, and gene amplifications were detected in ~40% of tbNGS and ~22% of pbNGS tests. MET amplifications (range: 2 - 40 copies (pbNGS) and 6 - 82 copies (tbNGS)) and ERBB2 amplifications (range: 2.1 - 90.2 copies (pbNGS) and 4 - 293 copies (tbNGS)) were detected in 1.6% (MET-tbNGS) and 4.6% (MET-pbNGS) and 4.2% (ERBB2-tbNGS) and 2.69% (ERBB2-pbNGS) of patients, respectively, and informed clinical trial enrollment. Of the fusions detected, 28 NTRK rearrangements were detected (NTRK1 – 16, NTRK2 – 5, NTRK3 – 7) by tissue-based testing and 3 (NTRK1) fusions were detected by plasma-based tests. Conclusions: These data describe the mutational landscape of NGS tests ordered within community oncology practices. SC’s data infrastructure links NGS-based testing data and clinical data to support real world evidence research, and highlights the need for healthcare IT systems to marry clinical and genomic data for clinical decision support and clinical research. [Table: see text]

Mutational analysis of >14,000 solid tumor NGS tests from community oncology practices: The Sarah Cannon molecular landscape.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18065-e18065
Author(s):  
Andrew McKenzie ◽  
Daniel Schlauch ◽  
Yasha Sharma ◽  
Shaita Picard ◽  
Connor Higgins ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mutational Analysis ◽  
Clinical Trial Design ◽  
Standard Of Care ◽  
Clinical Decision ◽  
Data Infrastructure ◽  
It Systems ◽  
Community Oncology ◽  
Real World Evidence ◽  
Molecular Landscape

e18065 Background: Utilization of NGS-based testing for patients in community oncology settings continues to grow. A comprehensive analysis of the molecular landscape of > 14,000 patients with commercial tissue-based and plasma-based NGS (tbNGS and pbNGS) testing from Sarah Cannon’s (SC) network of community oncologists between 2012 and 2018 was performed. These data aid clinical trial design/feasibility and identify rare and actionable mutations in the community oncology setting. Methods: Medical Oncologists in the SC network ordered NGS-based molecular profiling for their patients as standard of care. Data from multiple commercial vendors starting in 2012 were harmonized and analyzed. Results: On average, tbNGS (n = 8938) and pbNGS (n = 5419) tests revealed 14 and 4 mutations/sample, respectively. The top 10 mutated genes from both tbNGS and pbNGS - tests are in the table. The most predominant mutation-types detected were SNVs in both tbNGS and pbNGS tests, and gene amplifications were detected in ~40% of tbNGS and ~22% of pbNGS tests. MET amplifications (range: 2 - 40 copies (pbNGS) and 6 - 82 copies (tbNGS)) and ERBB2 amplifications (range: 2.1 - 90.2 copies (pbNGS) and 4 - 293 copies (tbNGS)) were detected in 1.6% (MET-tbNGS) and 4.6% (MET-pbNGS) and 4.2% (ERBB2-tbNGS) and 2.69% (ERBB2-pbNGS) of patients, respectively, and informed clinical trial enrollment. Of the fusions detected, 28 NTRK rearrangements were detected (NTRK1 – 16, NTRK2 – 5, NTRK3 – 7) by tissue-based testing and 3 (NTRK1) fusions were detected by plasma-based tests. Conclusions: These data describe the mutational landscape of NGS tests ordered within community oncology practices. SC’s data infrastructure links NGS-based testing data and clinical data to support real world evidence research, and highlights the need for healthcare IT systems to marry clinical and genomic data for clinical decision support and clinical research. [Table: see text]

Effect of prophylactic dextrose gel on the neonatal gut microbiome

2021 ◽  
pp. fetalneonatal-2021-322757
Author(s):  
Sophie L St Clair ◽  
Jane E Harding ◽  
Justin M O’Sullivan ◽  
Gregory D Gamble ◽  
Jane M Alsweiler ◽  
...  
Keyword(s):  
Microbial Community ◽  
Relative Abundance ◽  
Gut Microbiome ◽  
Beta Diversity ◽  
Alpha Diversity ◽  
Community Stability ◽  
Neonatal Hypoglycaemia ◽  
Bacterial Dna ◽  
Dna Concentration ◽  
Stool Samples

ObjectiveTo determine the effect of prophylactic dextrose gel on the infant gut microbiome.DesignObservational cohort study nested in a randomised trial.SettingThree maternity hospitals in New Zealand.PatientsInfants at risk of neonatal hypoglycaemia whose parents consented to participation in the hypoglycaemia Prevention in newborns with Oral Dextrose trial (hPOD). Infants were randomised to receive prophylactic dextrose gel or placebo gel, or were not randomised and received no gel (controls). Stool samples were collected on days 1, 7 and 28.Main outcome measuresThe primary outcome was microbiome beta-diversity at 4 weeks. Secondary outcomes were beta-diversity, alpha-diversity, bacterial DNA concentration, microbial community stability and relative abundance of individual bacterial taxa at each time point.ResultsWe analysed 434 stool samples from 165 infants using 16S rRNA gene amplicon sequencing. There were no differences between groups in beta-diversity at 4 weeks (p=0.49). There were also no differences between groups in any other microbiome measures including beta-diversity (p=0.53 at day 7), alpha-diversity (p=0.46 for day 7 and week 4), bacterial DNA concentration (p=0.91), microbial community stability (p=0.52) and microbial relative abundance at genus level. There was no evidence that exposure to any dextrose gel (prophylaxis or treatment) had any effect on the microbiome. Mode of birth, type of milk fed, hospital of birth and ethnicity were all associated with differences in the neonatal microbiome.ConclusionsClinicians and consumers can be reassured that dextrose gel used for prophylaxis or treatment of neonatal hypoglycaemia does not alter the neonatal gut microbiome.Trial registration number12614001263684.

scholarly journals Quxie Capsule Modulating Gut Microbiome and Its Association With T cell Regulation in Patients With Metastatic Colorectal Cancer: Result From a Randomized Controlled Clinical Trial

2020 ◽  
Vol 19 ◽  
pp. 153473542096982
Author(s):  
Lingyun Sun ◽  
Yunzi Yan ◽  
Dongmei Chen ◽  
Yufei Yang
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Gut Microbiome ◽  
Control Group ◽  
Controlled Clinical Trial ◽  
Th Cells ◽  
Microbiome Analysis ◽  
Xiyuan Hospital ◽  
Stool Samples

Aim: Quxie capsule(QX), a TCM compound, had shown benefit on survival outcomes for metastatic colorectal cancer(mCRC) patients and could inhibit tumor growth through immune regulation. This study aimed to evaluate whether such effect is associated with gut microbiome modulation. Method: We conducted a randomized double-blinded placebo controlled clinical trial in Xiyuan Hospital, China Academy of Chinese Medical Sciences. All patients were randomly assigned into QX or placebo control group. Before and after 1-month interventions, we collected patients’ stool samples for microbiome analysis by 16s rRNA sequencing approaches, as well as blood samples to analyze T lymphocyte subsets by flow cytometry methods. Microbiome analysis among groups was done through bioinformation analysis platform. The study had been proved by the ethics committee of Xiyuan Hospital (2016XLA122-1) had been registered on Chinese Clinical Trial Registry (registration number: ChiCTR2000029599). All patients consented before enrollment. Results: We randomly assigned 40 patients and 34 were finally analyzed. Among them, 29% were female, with an average age of 63 years old, and 74% had liver or lung metastasis. Both CD4 T(TH) cell and CD8 T(TC) cell counts increased after QX treatment, while TH cells were significantly more in QX than in control group (737 vs 449, P = .024). Microbiome community analysis on Class level showed that the proportion of Actinobacteria declined in the control group, but significantly increased after QX treatments (0.83% vs 4.7%, P = .017). LEfSe analysis showed that after treatments, samples from QX group were highly related with Oscillibacter, Eubacterium, and Lachnospiraceae. RDA analysis showed that after QX interventions, stool samples and microbiome species had relevance with TC/TH cells counts but were not statistically significant. Heatmap analysis on Genus level revealed that after QX treatments, higher amounts of TH cells were significantly associated with less abundance of g_Bifidobacterium (coef. −0.76, P = .002), Collinsella (coef.−0.61, P = .02), Ruminiclostridium_9 (coef. −0.64, P = .01). Conclusion: QX capsule could enhance TH cells level among mCRC patients and increase the abundance of gut anticancer bacteria such as Actinobacteria as well as butyrate-producing bacteria such as Lachnospiraceae. These results indicated that QX capsule might have the property of dual effects of antitumor and immunity enhancement, both mediated by the microbiome.

THU0303 Longitudinal Patterns in SLE Response To Standard of Care Therapy: Implications for SLE Clinical Trial Design

2016 ◽  
Vol 75 (Suppl 2) ◽  
pp. 296.3-297
Author(s):  
M. Kim ◽  
J.T. Merrill ◽  
K.C. Kalunian ◽  
B.H. Hahn ◽  
A. Roach ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Standard Of Care ◽  
Longitudinal Patterns

scholarly journals Gut Microbiome in Survivors of Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1384-1384
Author(s):  
Ronay Thomas ◽  
Wendy Shukwan Wong ◽  
NIccole Piguet ◽  
Jennifer Dean ◽  
Alissa Mills ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Gut Microbiome ◽  
Negative Binomial ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Alpha Diversity ◽  
Metabolic Derangement ◽  
Childhood All ◽  
Stool Samples

Abstract Purpose Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood and has a high treatment success rate. However, survivors of childhood ALL have a high prevalence of chronic medical illnesses, such as metabolic syndrome. Dysbiosis in the gut microbiome is associated with metabolic derangement and disease risk. Chemotherapy and antibiotics increase gut microbiome dysbiosis. We tested the hypothesis that ALL treatment can cause alterations in the gut microbiome that persist in survivorship. Method Stool samples were collected on fecal occult blood test cards from 38 survivors between 2-18 years of age who were >1 year off therapy for ALL. 16 stool samples from healthy siblings age 2-18 years were collected from 14 families as controls. Clinical data including anthropometrics, antibiotic use, and probiotic use were collected. DNA was extracted and sequenced using a modified Illumina 16S Metagenomics Sequencing Library Preparation protocol for analysis of hypervariable region V4. A single rarefaction was performed at 4,897 removing 2 samples with low mapped read counts. Alpha and beta (Bray) diversities were calculated; Wilcoxon rank-sum test was used to compare the alpha diversities between groups, as well as the beta diversities within and between groups. Wilcoxon signed-rank test was used to compare the alpha diversity between survivors and their matched siblings. Finally, read counts for each Operational Taxonomic Unit (OTU) was normalized and tested for differential abundance using edgeR, assuming a negative binomial model. Results Significant differences in the abundance of taxa were found, with the most notable being the depletion of Faecalibacterium in survivors (FDR= 0.0004). Figure 1 shows a heatmap with the complete linkage clustering method on the Euclidean distance using the 13 OTUs with statistically significant (FDR<0.05) differences between survivors and siblings (Table 1). When compared to their respective siblings, survivors exhibited decreased alpha diversity using four metrics (Observed, Shannon, Simpson, Fisher), but these results did not meet statistical significance. Significant differences were not observed in alpha diversity within survivors between different clinical categories (antibiotic usage, probiotic usage, disease risk, age at diagnosis and time off treatment). Stool microbiome was more similar within a family than between families (P = 0.00079). Conclusion Differences in the relative abundance of certain taxa were found between survivors and siblings. Specifically, Fecalibacterium was depleted in survivors, which has also been previously observed in older populations of childhood ALL survivors. This study shows that these microbiome changes are present in ALL survivors during childhood, and should be evaluated longitudinally for association with the chronic medical illnesses seen in ALL survivors in adulthood. Early interventions to restore the gut microbiome in ALL patients may potentially ameliorate the risk of long-term adverse health outcomes. Disclosures No relevant conflicts of interest to declare.

A phase II study to evaluate the need for > two doses of nivolumab + ipilimumab combination (combo) immunotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10003-10003 ◽  
Author(s):  
Michael A. Postow ◽  
Debra A Goldman ◽  
Alexander Noor Shoushtari ◽  
Allison Betof Warner ◽  
Margaret K. Callahan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Tumor Burden ◽  
Stage Iii ◽  
Recist 1.1 ◽  
Unresectable Stage ◽  
Secondary Endpoints ◽  
Prospective Trials ◽  
Grade 3 ◽  
Reduced Toxicity

10003 Background: Standard of care nivolumab (nivo) + ipilimumab (ipi) combo immunotherapy is given for 4 doses in patients (pts) with unresectable stage III/IV melanoma. Whether 4 doses are needed is questionable as retrospective data suggest pts treated with <4 doses of combo due to toxicity can have durable benefit. No prospective trials have evaluated the efficacy of intentionally giving <4 doses of combo in unresectable stage III/IV melanoma. Methods: In this phase 2, multicenter clinical trial (n=60), pts with unresectable stage III/IV melanoma received 2 doses of nivo (1mg/kg) + ipi (3mg/kg) followed by a CT scan at week 6. Pts with complete (CR) or partial responses (PR) by RECIST 1.1 or stable disease without an increase in total measurable tumor burden had protocol defined early favorable anti-tumor effect (FATE) and ceased combo, transitioning to maintenance nivo. Pts without FATE at week 6 received the standard third and fourth doses of combo followed by maintenance nivo. The primary endpoint was response rate by RECIST 1.1 at week 12. Secondary endpoints included additional efficacy assessments and safety. Results: 41 pts (68%) had FATE at week 6. The best overall response rates (CR + PR) by RECIST at week 12 or any time afterwards were 48% (95% CI: 35.2-61.6%) and 53% (95% CI: 40.0-66.3%), respectively. 18%, 58%, 12%, 10% had 1, 2, 3, 4 doses of combo, respectively. With a median follow-up of 11 months, any grade treatment-related toxicity occurred in 100% (57% grade 3-4) of pts. Three pts died due to treatment-related toxicity (2 myocarditis, 1 possible adrenal insufficiency). Among the 19 pts without FATE at week 6 and not selected to de-escalate combo after dose 2, no pts ultimately responded with ongoing combo dosing. Conclusions: The first 2 doses of nivo + ipi appear to drive combo’s response efficacy and toxicity. Early radiographic imaging at week 6 may be able to identify pts who do not respond to combo dosing beyond dose 2. Randomized studies are planned to evaluate 1 dose of combo to see if efficacy is maintained with reduced toxicity. Clinical trial information: NCT03122522.

Barriers to patient accrual in Ontario oncology clinical trials: Attitudes of oncologists and clinical research personnel.

2012 ◽  
Vol 30 (34_suppl) ◽  
pp. 36-36
Author(s):  
Ammar Bookwala ◽  
Daisy Dastur ◽  
Audrey Wong ◽  
Christina Marchand ◽  
Jalal Ebrahim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Research ◽  
Trial Design ◽  
Demographic Data ◽  
Clinical Trial Design ◽  
Standard Of Care ◽  
Medical Specialty ◽  
Research Personnel ◽  
Patient Accrual

36 Background: The medical specialty of oncology relies heavily on clinical trials to advance policies and practices related to cancer care. However, oncology clinical trial accrual in Ontario has dropped from 12.4% in 2007, to 8.5% in 2009. The objective of this study was to determine barriers experienced by Oncologists and Clinical Research Personnel (CRP) in recruiting patients to oncology trials in Ontario. Methods: In June 2012, an electronic survey was emailed to about 400 oncologists and CRP across Ontario. Variables of interest included demographic data, clinical trial involvement, and perceived barriers to participation in clinical trials amongst three previously identified barrier domains. Barriers were ranked, from 1 (least significant) to 5 (most significant). Statistics were compiled using Graphpad Prism software. Differences in responses were analyzed using the Kruskal – Wallis test and Dunn’s Multiple Comparison Test. Results: Of the 400 emails sent, there were 126 respondents (32%). Of the 126 respondents, 82 fully completed the survey (64.6% useable response rate). Amongst system related barriers, “time related” (Median Agreement (M): 4, Inter Quartile Range (IQR): 3-5), and “resource related” barriers (M: 4, IQR: 3-5) had the most negative effect on accrual (p<0.05). Amongst trial design barriers, “Relevance to patient population” (M: 3, IQR: 3-5), “Deviation from Standard of Care” (M: 3, IQR: 3-5) and “Complexity of Trial Protocol” (M: 4, IQR: 3-5) were the most significant barriers (p<0.05). Lastly, amongst personal barriers, “Commitment of the Principal Investigator/Research Staff” (M: 4, IQR: 3-5) and Drug Safety (M: 4, IQR: 2-4) were the most significant barriers to recruitment (p<0.05). Conclusions: Multiple barriers were identified as having a significant impact on patient accrual in clinical trials. Addressing these barriers prospectively in clinical trial design may benefit future studies to successfully accrue cancer patients. Also, creating clinical trial collaboration vehicles amongst sites in similar geographical areas may contribute to improving patient accrual to clinical trials.

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