RGX-202, a small-molecule creatine transporter SLC6A8 inhibitor, suppresses colorectal cancer and modulates human creatine levels.
Background: RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. Binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104. We previously reported results of the RGX-104 monotherapy dose escalation for which 26 patients with refractory solid tumors were treated in 5 dose cohorts. On-target AEs included hyperlipidemia and neutropenia. Flow-cytometry demonstrated MDSC depletion with associated T cell activation, which correlated with clinical benefit. A 40% disease control rate (DCR; SD+PR) was observed with a confirmed partial response (PR) by irRC (>79% reduction in index lesions) in a patient with platinum-refractory small cell lung cancer (SCLC). Methods: Here, we present the safety, biomarker and efficacy results of the docetaxel combination arm of the RGX-104 trial. Cohort 1- RGX-104 80 mg BID, and docetaxel at 35 mg/m2 days 1, 8, and 15 of a 28-day cycle; Cohort 2- RGX-104 80 mg BID, 5 days-on/2 days-off (5/2), and docetaxel at 28 mg/m2 on above schedule. Cohort 3- RGX-104 100 mg BID (5/2), and docetaxel as per cohort 2. Results: As of February 7, 2020, 11 patients with refractory solid tumors have been treated in 3 dose escalation cohorts with RGX-104 plus docetaxel. AEs were consistent with the individual toxicity profiles of docetaxel and RGX-104, with neutropenia being the most common AE and dose-limiting in cohort 1. The 5/2 dosing regimen in cohorts 2 and 3 resulted in significantly fewer episodes of neutropenia and no DLTs, while maintaining pharmacodynamic effects including >50% sustained MDSC depletion. A 66% DCR was observed in 9 evaluable patients including 2 patients in cohort 2 with PRs, a CPI-refractory SCCHN patient and a CPI-refractory melanoma patient, who remains on treatment at 36 weeks. A patient with melanoma in Cohort 3 had an initial assessment of SD and continues on study at 14 weeks. Clinical responses were associated with increases in T cell activation markers exceeding that generally observed with RGX-104 alone (up to a 5-fold increase in total CD8 T cells, a 7-fold increase in LAG-3+ CD8 T cells, and a 75-fold induction of serum IFNγ). Conclusion: The safety profile and marked pharmacodynamic and clinical activity of the RGX-104/docetaxel combination in CPI-refractory patients supports further development of this regimen. Consequently, the RGX-104/docetaxel regimen will be evaluated in a Phase 1b/2 expansion cohort in patients with relapsed/refractory ES-SCLC/high grade-neuroendocrine tumors. Citation Format: Emerson Lim, Erika P. Hamilton, Rebecca Redman, Michael A. Postow, Russell J. Schilder, Monica M. Mita, Alain C. Mita, Bartosz Chmielowski, James Strauss, Angela Jain, Shubham Pant, Olivier Rixe, Tomislav Dragovich, R. Donald Harvey, Igor Puzanov, Kevin B. Kim, Eric K. Rowinsky, Michael Szarek, Foster Gonsalves, Isabel Kurth, Celia Andreu, Robert W. Busby, David Darst, Masoud Tavazoie, Syed Raza, Narayan Lebaka16, Robert Wasserman, Gerald Falchook. RGX-104, a first-in-class immunotherapy targeting the liver-X receptor (LXR): Initial results from the phase 1b RGX-104 plus docetaxel combination dose escalation cohorts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT146.
Objectives: To compare the effect of active and secondhand smoke to unexposed smoke and to renal functions in young healthy Medical Students. Study Design: Cross sectional study comparative. Setting: Mohi-ud-din Islamic-Medical-College Mirpur AJ&K. Period: Fanuary-2018 to February-2019. Material & Methods: 350 healthy medical students aged 17-19 years were divided into active, secondhand and unexposed to smoke on basis of serum cotinine levels. The estimated GFR was measured by Modification of Diet in Renal Disease equation, albuminuria by albumin to urinary creatinine ratio, BMI by body weight (kg) to height (m2) and blood pressure by mercury manometer. The chronic kidney disease was classified into low, moderate and high risk according to Kidney Disease: Improving-Global Outcomes-2012-guidelines. Results: Out of 350 participants, 49 were active and 126 were of secondhand smoke. Most were male, overweight or obese, have high systolic and diastolic pressure and decreased eGFR. The CKD prevalence was 8.2%, eGFR <60ml/min/1.73 m² noticed in 19% and albuminuria in 26.4% of the participants. The proteinuria in active smokers in comparison with unexposed showed a high OR-5.67-(95%CI-17.17-40.49), cotinine levels >10 ng/mL; OR-5.520-(95%CI-3.67-3.91), systolic BP >140 mmHg; OR-2.50-(95%CI- 0.142-4.968); moderate to severely decreased eGFR, OR-2.478-(95%CI-0.124-4.391) and with high creatinine levels OR-4.300-(95%CI 2.432–7.603). The decreased eGFR showed Odds for obese OR-1.113(95%CI-2.391-5.197), active smokers OR-0.145(95%CI-0.029-0.721) and for systolic blood pressure >140 mmHg OR-6.892-(95%CI-1.414-2.235). Conclusion: Tobacco smoke exposure was associated with proteinuria and decreased eGFR effecting kidney functions in adolescents.
3504 Background: About 65% of advanced colorectal cancer (CRC) patients (pts) have creatine kinase B (CKB) expressing tumors. CKB expressing (CKB+) GI cancer cells import creatine via the creatine transporter SLC6a8 and utilize it to generate intracellular ATP. RGX-202, a small molecule inhibitor of SLC6a8, reduces intracellular creatine and ATP levels, leading to apoptosis. RGX-202 treatment triggers complete tumor regressions in multiple CKB+ preclinical models, including KRAS mutant CRC. Methods: RGX-202-001 is a phase I escalation/expansion study of RGX-202 +/- FOLFIRI in pts with advanced GI tumors. The primary safety objective during dose escalation is to identify the maximum tolerated dose (MTD), or the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed. The primary efficacy objective is to estimate the antitumor activity of RGX-202 by RECIST. Results: As of January 31, 2020, 17 pts have been treated in 4 single agent dose escalation cohorts: 600 mg BID (3 pts), 1200 mg BID (4 pts), 2400mg BID (5 pts) and 3600mg BID (5pts) given continuously. No DLTs were observed and an MTD was not reached. Treatment-related adverse events (TRAEs) occurring in > 2 pts are shown in the Table. There were no Grade 4 TRAEs. At the highest dose, 2 of 3 CRC pts had prolonged disease control: a patient with a KRAS G13D mutant cancer had SD for 14 weeks; and a patient with KRAS G12V mutant (MSS) cancer had a confirmed PR ongoing at 30 weeks. Exposure to RGX-202 was greater than dose-proportional and the average AUC0-24 ranged from ~15,700 ng-hr/mL in cohort 1 to 241,097 ng-hr/mL in in Cohort 4. Serum and urine creatine levels, pharmacodynamic markers of SLC6a8 inhibition, correlated with systemic exposure to RGX-202. Conclusions: Among 17 patients treated with single agent therapy, no DLTs occurred; notably, exposures predicted to be sufficient to inhibit human tumor growth from preclinical models were achieved along with concomitant pharmacodynamic effects. These data, along with a durable PR observed in the highest dose cohort, support further development of RGX-202. Consequently, dose escalation in combination with FOLFIRI in patients with advanced GI cancers is underway with plans for expansion in CKB+ CRC pts. Clinical trial information: NCT03597581 . [Table: see text]
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