Results: Of 348 pts (median age 69y, 43 e 85), 116 (33%) pts had two or more prior lines of tx, 209 (60%) had an ECOG score of 0-1, 48 (14%) had an ECOG score of 2+, and 91 (26%) had missing scores. 220 (63%) initiated tx at 70mg/m 2 and 128 (37%) initiated at <65mg/m 2 . 83 (38%) 70mg/m 2 and 26 (20%) <65mg/m 2 pts experienced a DR. Among pts who initiated at 70mg/m 2 , those with a DR had an mOS (95% CI) of 8.9 mos (7.3 e 10.8) and those without a DR had an mOS of 6.0 mos (4.8 e 7.2) [HR: 0.78 (0.56 e 1.09), adjusted HR: 0.77 (0.55 e 1.08)]. For pts who initiated at <65mg/ m 2 , mOS was 7.7 mos (5.0 e 14.9) for pts with a DR and 6.0 mos (4.7 e 7.2) for pts without [HR: 0.93 (0.55 e 1.56), adjusted HR: 0.83 (0.46 e 1.49)]. ECOG score (2+) and prior lines of tx (2) were associated with reduced survival among pts receiving 70mg/m 2 or <65mg/m 2 , respectively. Conclusions:In this real-world study of patients with mPDAC treated with a liposomal irinotecan based regimen for 3 cycles, DRs were associated with lower risks of death, though not statistically significant. Further studies are needed to characterize factors that influence clinical outcomes among liposomal irinotecan pts who receive DRs.Legal entity responsible for the study: Ipsen.
The use of plant-based medicine dates back centuries, and cannabis (Cannabis sativa) is one such plant that has been used medicinally and illicitly. Although cannabis contains hundreds of cannabinoids and other natural products, its potential medicinal use was largely ignored by modern researchers due to the legal restrictions and heavy regulations introduced in the 1930s. As restrictions on cannabis access have eased since the 1990s there is renewed interest in the research of cannabinoids and the other components in the cannabis plant. The focus of this review article is an overview of cannabis and the analytical challenges in the quality control and biological analysis. The pharmacological effects of psychoactive cannabinoids, delta-9-tetrahydrocannabinol (Δ9-THC) and delta-8-trans- tetrahydrocannabinol (Δ8-THC) is discussed, along with an abundant non-intoxicating cannabinoid, cannabidiol (CBD). The analytical methods for the quality control assays of cannabis products include gas chromatography and liquid chromatography coupled to different detectors, including mass spectrometry. This review will highlight various analytical methods for the quality control of cannabis products and the quantitation of cannabinoids in biological matrices for forensics and toxicology.
Background: NOX-A12 (olaptesed pegol) is a novel inhibitor of the chemokine CXCL12, ligand for CXCR4 and CXCR7, for treatment of solid tumors. Binding of the CXCL12 ligand by NOX-A12 prevents receptor engagement and also blocks the ability of CXCL12 to create a chemotactic concentration gradient by neutralization of the anchor domain. CXCL12 in complex with NOX-A12 has an increased half-life relative to unbound CXCL12, and as such increased CXCL12 levels are a marker of inhibition. The OPERA study (NCT03168139) is a phase 1/2 open-label clinical study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 and safety and efficacy of a combination of NOX-A12 with pembrolizumab in advanced MSS, metastatic colorectal and pancreatic cancer with liver metastasis. The study comprises two weeks of NOX-A12 monotherapy followed by repeated 21-day cycles of NOX-A12 plus pembrolizumab. Here we present pharmacodynamic biomarker data from for monotherapy phase with NOX-A12 as well as safety for the combination with pembrolizumab. Methods: Patients received 300 mg NOX-A12 by i.v. infusion on days 1, 4, 8, and 11 of the monotherapy phase. Needle biopsies were taken from suitable liver metastases before treatment and on day 14, peripheral blood was drawn at the same time points. Collected tumor samples were assessed for immune cell infiltration by IHC and cytokine signature using multiplex protein analysis. Results: At the time of abstract submission, 19 out of 20 patients have been recruited, 10 with colorectal and 9 with pancreatic cancer. Serial biopsies at baseline and end of monotherapy suitable for immunohistochemistry (IHC) and cytokine analysis were obtained from 12 out of 19 patients. CXCL12 levels were found to be increased in blood, but also in post-treatment tumor biopsies, suggesting penetration of NOX-A12 into the tumor. The comparison of cytokine levels in the currently available baseline tumor biopsies with those taken after two weeks of NOX-A12 monotherapy revealed changes in markers that are consistent with a Th1-like immune response in multiple patients. In particular IFN-γ, IL-2 and TNF-β were increased, accompanied by an increase of CXCL9 and/or CXCL10 indicating simultaneous T-cell attraction, which indicates a tissue response to treatment with NOX-A12. However, there were also increased levels of IL-1α, IL-1β and IL-6 in a number of patients, indicating potential myeloid counter regulation. IHC analysis is ongoing, and results for all patients will be presented. Treatment with NOX-A12 monotherapy and in combination with pembrolizumab was generally safe and well tolerated (139 AEs in total, thereof 45% grade 1; 37% grade 2; 17% grade 3; no grade 4 and 1 % grade 5). Conclusions: NOX-A12 penetrates into the tumor where it binds and neutralizes CXCL12. Changes in the cytokine signature suggest that NOX-A12 modulates the tumor microenvironment and induces an immune-stimulatory Th1-like signature in multiple patients. The safety profile of NOX-A12 combined with pembrolizumab is consistent with that of pembrolizumab in advanced cancer patients. Citation Format: Niels Halama, Ulrike Prüfer, Anna Froemming, Diana Beyer, Dirk Eulberg, Jarl Ulf Jungnelius, Aram Mangasarian. Evaluation of tumor biomarkers in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer treated with the CXCL12 inhibitor NOX-A12 and preliminary safety in combination with PD-1 checkpoint inhibitor pembrolizumab [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B206.
BACKGROUND. NOX-A12 is an inhibitor of the chemokine CXCL12 for treatment of solid tumors. Binding of CXCL12 by NOX-A12 prevents receptor engagement and blocks the ability of CXCL12 to form a chemotactic concentration gradient. The Opera study (NCT03168139) is a Phase I/II study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination of NOX-A12 with pembrolizumab in metastatic microsatellite-stable colorectal (CRC) and pancreatic (PaC) cancer. METHODS. Patients received 300 mg NOX-A12 twice weekly during the two-week monotherapy phase. Biopsies were taken from liver metastases before treatment and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In the combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab until progression or intolerable toxicity. RESULTS. Recruitment and treatment of all patients is completed, follow-up is ongoing. Eleven of the patients had CRC and 9 PaC. Fifteen of the patients (75%) were male, with a median age of 62 (CRC) and 68 years (PaC). All patients were heavily pretreated with a median of 5 (CRC) and 3 lines (PaC) of prior treatment. Best responses to last prior treatment was progressive disease for all except one patient. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. Biopsies obtained at baseline showed that the mean T cell density at the invasive margin was 327 cells/mm², clearly below the 600 cells/mm² that are predictive for a good prognosis. However, 5 out of 20 patients (25%) achieved a stable disease, thereof 3 CRC and 2 PaC patients; 7 of the patients showed prolonged time on treatment versus the preceding line of therapy. Updated figures for progression-free survival and overall survival for the whole patient cohort will be presented. Additional characterization of immunosuppressive cells in tumor biopsies and the periphery is ongoing. CONCLUSIONS. In patients with microsatellite-stable metastatic pancreatic and colorectal cancer with impaired immune systems and a high tumor load that have failed multiple prior lines of therapy, NOX-A12 plus pembrolizumab shows induction of immune response, stable disease in 25% of patients, and prolonged time on treatment vs. prior therapy for 35% of patients. The safety profile of the combination therapy was consistent with that of pembrolizumab in advanced cancer patients. Citation Format: Niels Halama, Ulrike Pruefer, Anna Froemming, Diana Beyer, Dirk Eulberg, Jarl Ulf Jungnelius, Aram Mangasarian. Clinical outcome and safety in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer treated with the CXCL12 inhibitor NOX-A12 in combination with PD-1 checkpoint inhibitor pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT092.
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