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  • 1
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    Evaluating the impact of perioperative antibiotic prophylaxis on the microbiome in patients with cutaneous malignancy.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS9602-TPS9602
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS9602-TPS9602
    Abstract: TPS9602 Background: Preoperative antibiotic prophylaxis is commonly used to reduce surgical site infections (SSIs). However, the rate of SSIs following surgical procedures classified as clean is only 2-3%. Overuse of antibiotics is associated with several potential adverse effects, including dysregulation of the gut microbiome. Disruption of the composition and function of the native gut microbiota, referred to as dysbiosis, has been implicated in a number of inflammatory and autoimmune disorders, as well as gastrointestinal (GI) and non-GI cancers. Recent studies have demonstrated that antibiotics have a profound and persistent effect on the gut microbiota, as evidenced by diminished overall abundance and diversity, as well as alteration of community composition that includes a decreased relative abundance of bacteria in the Ruminococcaceae family. In melanoma, diversity of gut microbiota and relative abundance of Ruminococaceae have been linked to improved survival and enhanced response following immune checkpoint blockade. In this study, we seek to determine the impact of preoperative prophylactic antibiotic use on the gut microbiome in patients following surgery for stage I or II melanoma. Methods: In this non-comparative randomized pilot trial, the impact of prophylactic antibiotic use at the time of surgical intervention on gut microbiome diversity and composition will be studied. Patients diagnosed with clinical stage I or II melanoma undergoing wide excision with or without lymphatic mapping and sentinel lymph node biopsy are randomized 1:1 to either receive preoperative cefazolin or no preoperative antibiotics. Stool samples and peripheral blood are collected before surgery, the day of surgery (optional), on post-operative day 3 (optional), and 2 weeks and 3 months following surgery. The primary endpoint for the study is change in microbiome alpha diversity at 2 weeks following surgery. Secondary endpoints are change in relative abundance of microbes at 2 weeks and 3 months after surgery and SSI rates according to whether or not prophylactic antibiotics were administered at time of surgery. Exclusion criteria include recent antibiotic use (within 3 months), allergy to beta-lactam or cephalosporin antibiotics, increased risk of infection due to medical comorbidity or use of immunosuppressive medication. Enrollment began in October 2021. As of January 2022, 22 of 30 patients have been accrued to ensure complete sample collection for 20 patients. Study findings may inform a larger trial evaluating interventions to mitigate antibiotic impact. Clinical trial information: NCT04875728.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS9602
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Identifying gut microbial signatures associated with B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) in response to immune checkpoint blockade (ICB).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 2511-2511
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 2511-2511
    Abstract: 2511 Background: While ICB has significantly improved clinical outcomes across several cancer types, only 15-20% of patients develop a durable response. Thus, novel and targetable biomarkers are needed. There is increased appreciation of the role of the gut microbiome, and TLS and B-cells in the TME in response to ICB. Here, we investigate the association between these two determinants of response in patient specimens from three randomized phase 2 neoadjuvant ICB trials of nivolumab +/- ipilimumab (melanoma (MEL; NCT02519322; n=23), non-small-cell lung cancer (NSCLC; NCT03158129; n=31), sarcoma (SARC; NCT02301039; n=17). Methods: Patients were categorized as responders (R) or non-responders (NR) based on major pathologic response, as defined in each histotype (MEL and NSCLC viable tumor ≤10%; SARC hyalinization 〉 30%). Baseline fecal samples were profiled via 16S rRNA gene sequencing from all three cohorts to assess the composition of patient gut microbiomes. Transcriptional profiles of biopsies collected pre-ICB for MEL and SARC, and post-ICB for MEL, SARC, and NSCLC were used to assess TLS (CXCL13, CCL18, CCL19, CCL21) and B-cell (PAX5, CD79B, CR2, MS4A1) signatures in the TME, by calculated mean values of normalized gene expressions. Comparison between samples were carried out using the Wilcoxon signed-rank test. Results: There were 21 R overall (NSCLC n=9; MEL n=9; SARC n=3). Despite significant differences in alpha and beta diversity across cohorts, relative abundance of Ruminococcus was significantly higher in R (p=0.003; NSCLC p 〈 0.001; MEL p=0.049; SARC p=0.7). B-cell signature was significantly higher post-ICB in R (R vs NR, post, TLS p=0.13; B-cell p=0.003), with consistent trends in each cohort. Longitudinal evaluation of transcriptional profiles showed that expression of TLS and B-cell signatures increased with treatment in R (pre vs post, MEL and SARC; TLS p=0.0098; B-cell p 〈 0.001) but not NR (pre vs post; TLS p= 0.87; B-cell p= 0.15), with consistent trends in sarcoma and melanoma subgroups. Combined correlative analysis with matched specimen showed that patients with higher pre-ICB relative abundance of Ruminococcus (above median) had significant increase in B-cell signatures (pre vs post, MEL and SARC; TLS p=0.052; B-cell p=0.002) which was not seen in patients with low abundance (below median) of Ruminococcus (pre vs post, MEL and SARC; TLS p=0.56; B-cell p=0.69). Conclusions: Unifying signatures in the gut microbiome are associated with response to ICB and increased B-cell infiltration and TLS formation in the TME. We expect these findings to energize mechanistic studies and new microbiome-based interventional approaches to improve clinical outcomes with ICB. Clinical trial information: NCT02519322, NCT03158129, NCT02301039.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.2511
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 11505-11505
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 11505-11505
    Abstract: 11505 Background: is a randomized, phase II non-comparative trial evaluating the efficacy of neoadjuvant checkpoint blockade [nivolumab (N) or ipilimumab/ nivolumab (I/N)] in patients (pts) with surgically resectable retroperitoneal DDLPS or extremity/truncal UPS treated with concurrent neoadjuvant radiation therapy (RT, UPS only). Methods: Primary endpoint was pathologic (path) response. Secondary endpoints were safety, RECIST response, recurrence-free survival, overall survival and patient-reported outcomes. Biospecimens (tumor, blood, fecal microbiome) at baseline, on therapy, and at time of surgery were collected and will be assessed for immune-based prognostic biomarkers. We assessed correlation between radiographic and pathologic response by linear regression. Correlative analyses includes assessment of tumor PD-L1 expression, characterization of tumor immune infiltrates by multiplex immunohistochemistry, and transcriptomic and genomic analyses. Results: Of the 25 pts enrolled; 24 are evaluable for response (14 DDLPS, 9 UPS). Clinical activity was variable by histologic subtype and treatment with RT. Median path response in the UPS cohort was 95% [95% CI 85–99] and was similar between the N/RT and I/N/RT groups (Table). Median path response in the DDLPS cohort was 22.5% [95% CI 85–99; Table]. Median change in tumor size (radiographic response) was -4% and +9% in the UPS and DDLPS cohorts, respectively. There was no correlation between path response and radiographic response (R 2 0.0309; p = 0.43). Of 8 pts with path response ≥ 85%, there was 1 partial response, 5 stable disease and 2 progressive disease by RECIST criteria. There was 1 delay to surgery due to grade 3 hyperbilirubinemia (Arm B). There was no difference in toxicity between N/RT and I/N/RT. Conclusions: N/RT and I/N/RT have significant clinical activity in UPS; more than expected compared to historic controls. Toxicity profiles were as expected and the majority of patients underwent resection without delay. Larger studies evaluating N/RT in UPS are warranted given the significant path response in this cohort. RECIST was not associated with path response and better markers of on-treatment clinical activity are needed. Correlative analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT03307616 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.11505
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Loss of the DNA repair gene RNase H2 and a unique subset of DDR-deficient leiomyosarcomas.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 11549-11549
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 11549-11549
    Abstract: 11549 Background: Targeting the DNA damage response (DDR)/Homologous Recombination (HR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS). Loss of RNase H2 decreases DNA repair via the Non-Homologous End-Joining (NHEJ) pathway, leading to increased double stranded breaks, replication stress, and increased cell death. Therefore, we developed an assay to screen for RNase H2 loss in STS patient samples to determine its prevalence and prognostic significance, particularly in LMS patients. Methods: RNASEH2B homozygous deletion (HomDel) calls from TCGA samples were based on the Allele-Specific Copy number Analysis of Tumors (ASCAT2) algorithm. Immunohistochemistry (IHC) of RNase H2 was performed on tissue microarrays (TMAs) of uterine (U-LMS) and soft tissue (ST-LMS) leiomyosarcoma samples from MD Anderson Cancer Center (MDACC) using a selective antibody developed by Repare Therapeutics. RNase H2 loss was defined as 〈 = 10% cells without nuclear IHC staining and scored by experienced pathologists in 2 separate cohorts. Genomic analysis was performed using SNiPDx™, a targeted-NGS assay designed to detect biallelic loss of function in select DDR related genes and whole genome sequencing (WGS). MDACC TMA samples were clinically annotated by retrospective review. Results: Using TCGA data, RNASEH2B HomDels were seen in 6% (5/80) of all LMS cases, with a higher proportion in U-LMS (15%; 4/27) as compared to ST-LMS (2%; 1/53). In a pan-tumor TMA, RNase H2 loss by IHC was found in 3.8% (32/843) of samples overall, and in 10% (9/88) of LMS samples. This proportion of RNase H2 loss was higher in a larger MDACC LMS cohort, where negative staining of RNase H2 was found in 30% (33/110) of U-LMS and 38% (39/102) of ST-LMS cases. 30 MDACC LMS cases (15 U-LMS and 15 ST-LMS) were analyzed for RNASEH2B HomDels by SNiPDx. In U-LMS, RNASEH2B HomDels were detected in 64% (7/11) of RNase H2 IHC loss cases vs. 0% (0/3) in RNase H2 IHC intact cases. No RNASEH2B HomDels were detected in ST-LMS cases (10 IHC loss, 5 intact). The median overall survival (mOS) of MDACC U-LMS patients (n = 109) was 4.3 years. No significant mOS difference was seen in RNase H2 IHC intact cases versus loss (mOS 4.4 v 3.3 years, p = 0.54). In a separate cohort, 45 U-LMS samples were screened by IHC; 22% (10/45) had RNase H2 loss. RNASEH2B HomDels were detected in 70% (7/10) of RNase H2 IHC loss cases using SNiPDx and confirmed using WGS. In contrast, RNASEH2B HomDels were detected in 3% (1/33) of RNase H2 IHC intact cases. In the combined U-LMS cohort with IHC and SNiPDx results (n = 71), the diagnostic accuracy, sensitivity and specificity of RNase H2 IHC for detecting RNASEH2B HomDels was 76%, 93% and 71% respectively. Conclusions: RNase H2 loss via RNASEH 2B HomDels is prevalent in U-LMS and is unique from other DDR pathway alterations. RNase H2 IHC is an effective screening tool and is being developed for future clinical trials targeting DDR in LMS.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.11549
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Health-related quality of life in patients with resectable undifferentiated pleomorphic sarcoma treated with neoadjuvant checkpoint blockade in a single institution randomized phase II clinical trial.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 11544-11544
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 11544-11544
    Abstract: 11544 Background: In SARC028, patients with undifferentiated pleomorphic sarcoma (UPS) had a 40% overall response rate to pembrolizumab. Based on this, we conducted a randomized, phase II, non-comparative trial of combination nivolumab (nivo/RT) and ipilimumab (ipi/nivo/RT) and demonstrated an 89% major pathologic response. Here, we report the health-related quality of life (HRQoL) metrics. Methods: In this study (NCT03307616), patients with resectable UPS were randomized (1:1) to receive one dose of nivo (3mg/kg) or one dose of combination nivo (3 mg/kg) and ipi (1 mg/kg), followed by combination of nivo (3 doses, 3mg/kg every 2 weeks) plus 50 Gy in 25 fractions (both arms). HRQoL was assessed using the MD Anderson Symptom Inventory (MDASI), European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30, and the Functional Assessment of Cancer Therapy – General (FACT-G) questionnaires. Questionnaire completion rates were calculated using the number of patients with at least one baseline and post-baseline assessment. Analyses included mean change from baseline scores to week 11 (preoperative) and week 54 (postoperative). Results: Ten patients were randomized from October 2017 to February 2020. HRQoL were collected at baseline (n = 10) and at week 11 for five (83%) nivo/RT and three (60%) ipi/nivo/RT patients. Three (60%) nivo/RT and three (100%) ipi/nivo/RT patients had week 54 assessments. MDASI scores indicative of symptom severity and interference of daily life both decreased for patients undergoing ipi/nivo/RT (0.8→0.67 and 0.9→0.46, respectively) while both increased in the nivo/RT group (1.6→2.22 and 1.9→3.33, respectively). Both arms had similar increases at 54 weeks. Patients undergoing ipi/nivo/RT experienced a greater decline in EORTC-QLC global health status at 54 weeks than those undergoing single agent therapy (-22.92 vs -8.33). The mean change in total FACT-G score did not differ between the two arms at 11 weeks (-4.0 vs -4.5), however, there was a significant decline for patients undergoing ipi/nivo/RT at 54 weeks (-20.3 vs -5.7). Conclusions: For patients with resectable UPS, combination immune checkpoint blockade with ipi/nivo/RT is associated with an improvement in short term HRQoL compared to single-agent nivo/RT. This finding warrants further study with more patients, controlling for baseline symptom scores. Combination therapy was associated with a slower recovery to baseline function, with ongoing decline in HRQoL at 54 weeks post treatment. Our study demonstrates the feasibility of collecting HRQoL metrics, which can be key factors in guiding patient management decisions. Clinical trial information: NCT03307616.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.11544
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Preliminary results of phase 2 trial of preoperative image guided intensity modulated proton radiation therapy (IMPT) with simultaneously integrated boost (SIB) to the high-risk margin for retroperitoneal sarcomas (RPS).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 11550-11550
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 11550-11550
    Abstract: 11550 Background: RPS often have local recurrence (LR) after surgery. Preoperative radiation (RT) to 50.4 Gy can reduce LR risk but is not uniformly effective, especially after (+) margin resections. Therefore, we conducted a multi-institutional, prospective Phase II study to assess efficacy and tolerability of preop IMPT with selective dose escalation to 63 GyRBE to the posterior RPS margin (clinical target volume [CTV] 2) at high risk for (+) margins to further reduce the risk of LR. This dose was tolerable in a prior phase I study (DeLaney T et al, 2017, PMID:28740917). Methods: Primary RPS patients (pts) 〉 18 years received preop IMPT, 50.4 GyRBE in 28 fractions (fx) of 1.8 GyRBE to CTV1 (tumor plus adjacent tissue at risk of subclinical disease) with SIB to CTV2 to 63.0 GyRBE in 28 fx of 2.25 GyRBE. Pts with high-grade tumors could get chemotherapy(CTX) prior to IMPT. To avoid treatment delay, 11 fx of IMRT x-rays could be substituted for IMPT. Pts had restaging and surgery 4-8 weeks after IMPT. Primary study endpoint was local tumor control. Secondary endpoints included clinical and pathologic response, surgical margin status, and disease-free and overall survival. Results: We accrued 60 pts from January 2016 to February 2021. Histology: 35 liposarcoma(LPS) (19 dediff and 16 well diff), 22 leiomyosarcoma(LMS), and 3 undifferentiated pleomorphic sarcoma. IMPT was delivered per protocol in all pts. 51 pts have had surgery, 5 are awaiting surgery, and 4 had no surgery due to metastases(DM) on preop imaging. 22 pts had (+) margins. 2 pts had 〉 75% necrosis. With 23-month median (range 1-52 months) follow-up after start of RT, there were two LRs. A dediff LPS pt had a well diff LPS LR 26 months postop, resected, and is disease-free. A renal vein/IVC LMS pt treated with CTX and IMPT had LR and DM 4 months postop and died from disease. Surgical Clavien-Dindo morbidity scores: 0(21), 1(9), 2(8), 3a (4), 3b(4), 4a(2), 4(b)1, 5(2); the periop deaths were from sepsis(pneumonia) and duodenal ulcer. The grade 3-4 periop morbidity included abscess(3), treated by catheter(2) or operative(1) drainage, prolonged hospital stays (2 pts with IVC LMS), small bowel obstruction (1), and late sigmoid colon anastomotic failure (1). Readmissions for lymphopenia(1), pneumoperitoneum (1), and volume overload (1). One late neuropathy was seen in a Type II diabetic pt with transient postop weakness after femoral nerve dissection who later had significant lower extremity weakness 3.75 years postop. Study was amended to reduce IMPT dose in diabetic pts. Conclusions: Preoperative IMPT with selective dose escalation to 63 GyRBE to the high risk posterior RPS margin is feasible. Early local control results with this approach appear promising. Some peri-operative morbidity was noted but appears to be in the expected range for RPS resections. Clinical trial information: NCT01659203.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.11550
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Circulating melanoma cells and recurrence in stage III melanoma patients.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 9016-9016
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 9016-9016
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.9016
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Targeted next generation sequencing in well-differentated/dedifferentiated liposarcoma (WD/DD LPS): Multiple gene amplifications but few mutations.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 10550-10550
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 10550-10550
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.10550
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Initial results from a first in human dose escalation trial of a novel immune stimulating oncolytic adenovirus, AdAPT-001 TGF-ß Trap .
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2550-2550
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2550-2550
    Abstract: 2550 Background: As a class, oncolytic adenoviruses (OAV), modified agents of the common cold, specifically target and lyse tumor cells, and by expression of cytotoxic transgenes activate an immune response. AdAPT-001 is an OAV, which carries a transforming growth factor beta (TGF-ß) trap that neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. Preclinically, AdAPT-001 TGF-ß Trap eradicates non-T-cell infiltrated tumors. The aim of this Phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 TGF-ß Trap after single intra-tumoral injection (IT) (Phase 1a) and multidose IT injection (Phase 1b) in patients with advanced refractory solid tumors. Methods: This was an open label, single-arm, multicenter dose escalation design trial. AdAPT-001 TGF-ß Trap was administered by intratumoral injection. 9 patients were in a single-dose group, where doses of 2.5 x 10 11 , 5.0 x 10 11 , 1.0 x 10 12 viral particles (VPs), were tested, and 19 patients with a median age of 70, 5 median prior regimens, and a median ECOG score of 1 received AdAPT-001 every 2 weeks at 1.0 x 10 12 VPs until progression. Results: AdAPT-001 TGF-ß Trap was well tolerated with local inflammation, fever, and fatigue as the main side effects. No dose limiting toxicities, no grade 4 toxicities, or treatment-related serious adverse events (SAEs) were seen. Tumor types were sarcoma (n = 8), melanoma (n = 2), head & neck (n = 5), gastric (n = 1), rectal (n = 1), breast (n = 1), fallopian (n = 1). Biological activity (virus replication, local reactions, and tumor shrinkage) was observed. The duration of local reactions and virus replication suggested that dosing every 2 weeks was appropriate. The overall responses to treatment were as follows: 5 patients had durable stable disease for 6 months or more, 1 patient had a partial response, and 2 patients demonstrated pseudoprogression with inflammation of uninjected as well as the injected tumor, 5 patients had stable disease for approximately 2 months and 15 patients had progressive disease. 2 abscopal responses have been seen to date. The data also suggest a dose-response relationship, with higher and more frequent doses associated with better outcomes. Peripheral lymphocyte subset analysis and serum cytokine analysis are ongoing. Conclusions: AdAPT-001 TGF-ß Trap is well tolerated and no dose limiting toxicities were observed with the single or multidosing protocol described. Evidence of an antitumor effect was seen. The recommended Phase 2 dose was 1.0 x 10 12 VPs administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 TGF-ß Trap with a checkpoint inhibitor is planned. Clinical trial information: NCT04673942 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2550
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Loss of SMAD4 and effect on overall survival in resected gastrointestinal neuroendocrine tumors.
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 3_suppl ( 2014-01-20), p. 250-250
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 3_suppl ( 2014-01-20), p. 250-250
    Abstract: 250 Background: Studies by comparative genomic hybridization have demonstrated that the 18q chromosomal region is frequently lost in gastrointestinal neuroendocrine tumors (GI-NET). However, the impact of DPC/SMAD4 loss, which is located 18q21, in the pathogenesis of GI-NET remains controversial. In this study, we sought to determine the protein expression of SMAD4 in GI-NET and the impact on oncologic outcomes. Methods: To investigate the role of SMAD4 in GI-NET, a tissue microarray consisting of 33 GI-NET was constructed and analyzed by immunohistochemistry for SMAD4 expression. SMAD4 expression was classified as negative, SMAD4-low (≤10% cells +) or SMAD4-high ( 〉 10% cells+). Staining results were correlated clinicopathologic features and overall survival. Results: Of the 33 tumors examined, 93% were low- or intermediate-grade and 7% high-grade. 35% of GI-NET were negative for SMAD4, 45% were SMAD4-low and 15% SMAD4-high. Expression of Chromogranin was observed in 91% of all tumors, synaptophysin in 94%, CDX2 in 64%, and CK19 in 55%. We were unable to identify any association between loss of SMAD4 and stage or tumor grade. There was an inverse correlation between loss of SMAD4 and CK19 expression, whereby 75% of SMAD4-neg tumors expressed CK19 and only 32% of SMAD4+ expressed CK19 (p=0.01). At a median follow-up of 123 months, median overall survival was 203 months. Survival differences related to SMAD4 status resulted in clinically meaningful, although statistically non-significant, differences in overall survival (SMAD4-low: 132 months vs. SMAD4-high: 203 months, p=0.058). Conclusions: Differences in SMAD4 expression result in clinically important differences in overall survival, although this cohort may be underpowered to detect a statistically-significant difference. Future studies with larger patient populations may be critical to evaluate the importance of SMAD4 in the pathogenesis of GI-NET.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2014.32.3_suppl.250
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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