8 research outputs found
Effect of a chemical manufacturing plant on community cancer rates
BACKGROUND: We conducted a retrospective study to determine if potential past exposure to dioxin had resulted in increased incidence of cancer in people living near a former manufacturing plant in New South Wales, Australia. During operation, from 1928 to 1970, by-products of the manufacturing process, including dioxin and other chemical waste, were dumped into wetlands and mangroves, discharged into a nearby bay and used to reclaim land along the foreshore, leaving a legacy of significant dioxin contamination. METHODS: We selected 20 Census Collector Districts within 1.5 kilometres of the former manufacturing plant as the study area. We obtained data on all cases of cancer and deaths from cancer in New South Wales from 1972 to 2001. We also compared rates for some cancer types that have been associated with dioxin exposure. Based on a person's residential address at time of cancer diagnosis, or at time of death due to cancer, various geo-coding software and processes were used to determine which collector district the case or death should be attributed to. Age and sex specific population data were used to calculate standardised incidence ratios and standardised mortality ratios, to compare the study area to two comparison areas, using indirect standardisation. RESULTS: During the 30-year study period 1,106 cases of cancer and 524 deaths due to cancer were identified in the study area. This corresponds to an age-sex standardised rate of 3.2 cases per 1,000 person-years exposed and 1.6 deaths per 1,000 person-years exposed. The study area had a lower rate of cancer and deaths from cancer than the comparison areas. The case incidence and mortality due to lung and bronchus carcinomas and haematopoietic cancers did not differ significantly from the comparison areas for the study period. There was no obvious geographical trend in ratios when comparing individual collector districts to New South Wales according to distance from the potential source of dioxin exposure. CONCLUSION: This investigation found no evidence that dioxin contamination from this site resulted in increased cancer rates in the potentially exposed population living around the former manufacturing plant
Effect of a chemical manufacturing plant on community cancer rates
Abstract Background We conducted a retrospective study to determine if potential past exposure to dioxin had resulted in increased incidence of cancer in people living near a former manufacturing plant in New South Wales, Australia. During operation, from 1928 to 1970, by-products of the manufacturing process, including dioxin and other chemical waste, were dumped into wetlands and mangroves, discharged into a nearby bay and used to reclaim land along the foreshore, leaving a legacy of significant dioxin contamination. Methods We selected 20 Census Collector Districts within 1.5 kilometres of the former manufacturing plant as the study area. We obtained data on all cases of cancer and deaths from cancer in New South Wales from 1972 to 2001. We also compared rates for some cancer types that have been associated with dioxin exposure. Based on a person's residential address at time of cancer diagnosis, or at time of death due to cancer, various geo-coding software and processes were used to determine which collector district the case or death should be attributed to. Age and sex specific population data were used to calculate standardised incidence ratios and standardised mortality ratios, to compare the study area to two comparison areas, using indirect standardisation. Results During the 30-year study period 1,106 cases of cancer and 524 deaths due to cancer were identified in the study area. This corresponds to an age-sex standardised rate of 3.2 cases per 1,000 person-years exposed and 1.6 deaths per 1,000 person-years exposed. The study area had a lower rate of cancer and deaths from cancer than the comparison areas. The case incidence and mortality due to lung and bronchus carcinomas and haematopoietic cancers did not differ significantly from the comparison areas for the study period. There was no obvious geographical trend in ratios when comparing individual collector districts to New South Wales according to distance from the potential source of dioxin exposure. Conclusion This investigation found no evidence that dioxin contamination from this site resulted in increased cancer rates in the potentially exposed population living around the former manufacturing plant.</p
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383 Durable responses with intratumoral electroporation of plasmid interleukin 12 plus pembrolizumab in patients with advanced melanoma progressing on an anti-PD-1 antibody: updated data from keynote 695
Background
Electroporated plasmid interleukin-12 (pIL-12-EP; tavokinogene telseplasmid; TAVO) induces sustained intratumoral expression of IL-12, a cytokine that is integral for response to anti-PD-1 antibodies. Here, we present updated safety and response duration data from KEYNOTE 695, a Phase 2, multicenter, open-label trial of pIL-12-EP in combination with pembrolizumab in patients with stage III/IV melanoma immediately following confirmed progression on an anti-PD-1 antibody.
Methods
Patients with confirmed disease progression after ≥12 weeks‘ treatment with an anti-PD-1 antibody alone or in combination were eligible. Patients received intratumoral pIL-12-EP on days 1, 5 and 8 every 6 weeks and pembrolizumab 200 mg every 3 weeks. Responses were assessed by the investigator at 12-week intervals using RECIST v1.1; overall survival (OS) and duration of response (DoR) assessments were conducted using the Kaplan-Meier method.
Results
Of the first 56 patients treated, 50% had visceral disease (M1b-d), 80% had received 1–2 and 20% ≥3 prior lines of therapy, 27% had prior ipilimumab and 21% prior BRAF/MEK inhibitors. 61% of patients were primary refractory to anti-PD-1. 54 patients were efficacy evaluable, defined as patients who had at least one post-treatment scan. The investigator-assessed objective response rate (ORR) per RECIST was 27.8% (4 CR, 11 PR); ORR per iRECIST was 29.6%. In patients with M1b-d staging, ORR was 33.3% (n=9/27), and in those receiving prior ipilimumab, ORR was 33.3% (n=5/15). Seven patients had 100% reduction in target lesions, and regression was observed in non-injected lesions. The median DoR had not been reached. With a median follow up of 19.3 months, the median OS (95% CI) was 24.5 (14.4, NR) months (figure 1). The study is now fully enrolled. In 105 patients with safety data, there were no Grade 4/5 treatment-related adverse events (TRAEs) reported. Grade 3 TRAEs occurred in 5.7% and comprised cellulitis in two patients and arthralgia, pneumonitis, enteritis, keratoacanthoma, lichen planus and musculoskeletal chest pain in one patient each. The Grade 1/2 TRAEs in ≥10% patients were fatigue (27.6%), procedural pain (20.0%), diarrhea (17.1%), nausea (10.5%) and pruritus (10.5%). ORR by blinded independent central review has commenced and a global phase 3 trial is planned.
Abstract 383 Figure 1
Overall survival in patients treated with pIL-12-EP in combination with pembrolizumab. Dark grey bars: time on study treatment, light grey bars: end of treatment to death or censoring
Conclusions
Patients with anti-PD-1 therapy refractory advanced melanoma can achieve deep, durable responses in both injected and non-injected lesions with pIL-12-EP plus pembrolizumab. Intratumoral pIL-12-EP in combination with pembrolizumab was generally well tolerated, with minimal Grade 3 and no Grade 4/5 TRAEs.
Trial Registration
NCT03132675
Ethics Approval
The study was approved by a central IRB and/or local institutional IRB/Ethics Committee as required for each participating institution.
Consent
Written informed consent was obtained from the patients participating in the trial; the current abstract does not include information requiring additional consen
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799 Durable responses and immune activation with intratumoral electroporation of pIL-12 plus pembrolizumab in actively progressing anti-PD-1 refractory advanced melanoma: KEYNOTE 695 interim data
Background Electroporated plasmid IL-12 (TAVO or tavokinogene telseplasmid) is a novel pro-inflammatory intratumoral therapy with substantial single agent activity in melanoma, which has been shown to synergize with anti-PD-1 antibodies in patients predicted as non-responders to anti-PD-1.1 2 Interim data from patients with stage III/IV melanoma actively progressing on anti-PD-1 antibody are presented herein. Methods Patients with confirmed disease progression by RECIST v1.1 after at least 12 weeks of treatment on pembrolizumab or nivolumab (or combination checkpoint blockade) and within 12 weeks of last dose (with no intervening therapies) were enrolled. There was no limit on the number of prior lines of therapy. At least one accessible lesion was electroporated with plasmid IL-12 (pIL-12-EP) on days 1, 5 and 8 every 6 weeks and pembrolizumab was administered every 3 weeks. Tumor response in treated and untreated lesions was assessed by RECIST v1.1 every 12 weeks. Endpoints include ORR, safety, PFS, OS, and DOR. Results The first 56 patients treated of 100 planned were included in this interim analysis. Of these, 84% had Stage IV disease, 30% had M1c or M1d disease, and 27% had prior exposure to ipilimumab. In 54 efficacy evaluable patients the investigator-assessed ORR was 30% (3 CR/13 PR), 5 patients had 100% reduction of target lesions. All responses have been confirmed, only two responding patient progressed while on study, 2 patients completed the study with ongoing responses (figures 1 and 2). In patients with M1c/M1d disease, the ORR was 35.2% (n=6/17). Tumor reduction was observed in untreated lesions in 12 of 12 patients who had unaccessible lesions or accessible untreated lesions. The median overall survival (mOS) and duration of response (mDOR) has not been reached, with a median follow-up time of 13 months. Grade 3 treatment-related adverse events (TRAEs) were seen in 5.4% of patients, and there were no grade 4/5 TRAEs. The rate of grade 3 treatment-emergent (TEAEs) regardless of cause was 23.2%. The median time for pIL-12-EP treatment was 10 minutes (range 2,46). Consistent with prior studies of single-agent pIL-12-EP, tumor IHC, and transcriptomic assessments revealed hallmarks of antigen-specific antitumor immunity in this study. Additional analyses including microbiome, TCR clonality, and peripheral blood biomarker assays will be presented. Best confirmed overall response by RECIST v1.1 after confirmed progression on anti PD-1 data-icon-position= data-hide-link-title= 0 \u3e Download figure Open in new tab Download powerpoint Abstract 799 Figure 1 Best confirmed overall response by RECIST v1.1 after confirmed progression on anti PD-1 Percent change in sum of target lesions over time data-icon-position= data-hide-link-title= 0 \u3e Download figure Open in new tab Download powerpoint Abstract 799 Figure 2 Percent change in sum of target lesions over time Conclusions In this rigorously defined PD-1 antibody refractory patient population, the addition of pIL-12-EP to PD-1 antibody therapy induced deep, durable, systemic response in local treated and distant visceral metastatic untreated lesions with nominal systemic toxicity. Trial Registration Trial Registration: NCT#0313267