Browsing by Author "Logan, Theodore F."

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    Angiokines Associated with Targeted Therapy Outcomes in Patients with Non–Clear Cell Renal Cell Carcinoma
    (AACR, 2021-06) Armstrong, Andrew J.; Nixon, Andrew B.; Carmack, Andrea; Yang, Qian; Eisen, Tim; Stadler, Walter M.; Jones, Robert J.; Garcia, Jorge A.; Vaishampayan, Ulka N.; Picus, Joel; Hawkins, Robert E.; Hainsworth, John D.; Kollmannsberger, Christian K.; Logan, Theodore F.; Puzanov, Igor; Pickering, Lisa M.; Ryan, Christopher W.; Protheroe, Andrew; George, Daniel J.; Halabi, Susan; Medicine, School of Medicine
    PURPOSE: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. PATIENTS AND METHODS: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). RESULTS: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. CONCLUSIONS: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
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    Correction: Angiokines Associated with Outcomes after Sunitinib or Everolimus Treatment in Patients with Non–Clear Cell Renal Cell Carcinoma
    (AACR, 2021-06) Armstrong, Andrew J.; Nixon, Andrew B.; Carmack, Andrea; Yang, Qian; Eisen, Tim; Stadler, Walter M.; Jones, Robert J.; Garcia, Jorge A.; Vaishampayan, Ulka N.; Picus, Joel; Hawkins, Robert E.; Hainsworth, John D.; Kollmannsberger, Christian K.; Logan, Theodore F.; Puzanov, Igor; Pickering, Lisa M.; Ryan, Christopher W.; Protheroe, Andrew; George, Daniel J.; Halabi, Susan; Medicine, School of Medicine
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    A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer
    (American Association for Cancer Research, 2008-06) Robertson, Michael J.; Kirkwood, John M.; Logan, Theodore F.; Koch, Kevin M.; Kathman, Steven; Kirby, Lyndon C.; Bell, William N.; Thurmond, Linda M.; Weisenbach, Jill; Dar, Mohammed M.; Medicine, School of Medicine
    Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer. Experimental design: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements. Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 microg/kg (group A) or 100, 1,000, or 2,000 microg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, and IL-18-binding protein were observed following dosing. Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.
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    Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry
    (BMC, 2017-12-19) Curti, Brendan; Daniels, Gregory A.; McDermott, David F.; Clark, Joseph I.; Kaufman, Howard L.; Logan, Theodore F.; Singh, Jatinder; Kaur, Meenu; Luna, Theresa L.; Gregory, Nancy; Morse, Michael A.; Wong, Michael K. K.; Dutcher, Janice P.; Medicine, School of Medicine
    Background Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIMSM registry data base from 2008 to 2016 (NCT01415167, August 9, 2011). Methods Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. Results Median follow-up was 3.5+ years (range 1–8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIMSM patients): 99 (16%) in mM and 53 (5.8%) in mRCC patients. 31 irAEs occurred prior to IL-2, 24 during IL-2, and 97 after IL-2 therapy. 74 irAEs were attributed to IL-2 only (during/ after IL-2). Of the 97 post IL-2 irAEs, 24 were attributed to CPI, and 15 could not be distinguished as caused by IL-2 or CPI. Tumor control was 71% for those experiencing irAE, and 56% for those with no irAE (p = 0.0008). Overall survival was significantly greater for those experiencing irAEs during/ after IL-2 therapy, compared to those with no irAE or irAE before IL-2 therapy, in mM patients, median 48 months vs 18 months (p < 0.0001), and in mRCC patients, median 60 months vs 40 months (p = 0.0302), independent of CPI-related irAEs. IL-2-related irAEs were primarily vitiligo and thyroid dysfunction (70% of IL-2 related irAEs), with limited further impact. Conclusions irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response.
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    Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2
    (BMJ, 2021-02-04) Clark, Joseph I.; Curti, Brendan; Davis, Elizabeth J.; Kaufman, Howard; Amin, Asim; Alva, Ajjai; Logan, Theodore F.; Hauke, Ralph; Miletello, Gerald P.; Vaishampayan, Ulka; Johnson, Douglas B.; White, Richard L.; Wiernik, Peter H.; Dutcher, Janice P.; Medicine, School of Medicine
    High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.
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    Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody
    (AACR, 2017) Segal, Neil H.; Logan, Theodore F.; Hodi, F. Stephen; McDermott, David; Melero, Ignacio; Hamid, Omid; Schmidt, Henrik; Robert, Caroline; Chiarion-Sileni, Vanna; Ascierto, Paolo A.; Maio, Michele; Urba, Walter J.; Gandadhar, Tara C.; Suryawanshi, Satyendra; Neely, Jaclyn; Jure-Kunkel, Maria; Krishnan, Suba; Kohrt, Holbrook; Sznol, Mario; Levy, Ronald; Medicine, School of Medicine
    Purpose: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma. Experimental Design: A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose–escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatment-related and serious adverse events (AEs), as well as treatment-related AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs. Results: Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses ≥1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines. Conclusions: Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of ≥1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents.
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    Whole-body PET/CT evaluation of tumor perfusion using generator-based 62Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II): validation by direct comparison to 15O-water in metastatic renal cell carcinoma
    (Society of Nuclear Medicine and Molecular Imaging (SNMMI), 2015) Fletcher, James W.; Logan, Theodore F.; Eitel, Jacob A.; Mathias, Carla J.; Ng, Yen; Lacy, Jeffrey L.; Hutchins, Gary D.; Green, Mark A.; Radiology and Imaging Sciences, School of Medicine
    This study was undertaken to demonstrate the feasibility of whole-body (62)Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II) ((62)Cu-ETS) PET/CT tumor perfusion imaging in patients with metastatic renal carcinoma and to validate (62)Cu-ETS as a quantitative marker of tumor perfusion by direct comparison with (15)O-water perfusion imaging. Methods: PET/CT imaging of 10 subjects with stage IV renal cell cancer was performed after intravenous administration of (15)O-water (10-min dynamic list-mode study) with the heart and at least 1 tumor in the PET field of view, followed 10 min later by intravenous (62)Cu-ETS (6-min list-mode study). Whole-body (62)Cu imaging was then performed from 6 to 20 min at 2-3 min/bed position. Blood flow (K1) was quantified with both agents for normal and malignant tissues in the 21.7-cm dynamic field of view. The required arterial input functions were derived from the left atrium and, in the case of (62)Cu-ETS, corrected for partial decomposition of the agent by blood with data from an in vitro analysis using a sample of each patient's blood. This imaging protocol was repeated at an interval of 3-4 wk after initiation of a standard clinical treatment course of the antiangiogenic agent sunitinib. Results: All subjects received the scheduled (62)Cu-ETS doses for the dynamic and subsequent whole-body PET/CT scans, but technical issues resulted in no baseline (15)O-water data for 2 subjects. Direct comparisons of the perfusion estimates for normal tissues and tumor metastases were made in 18 paired baseline and treatment studies (10 subjects; 8 baseline studies, 10 repeated studies during treatment). There was an excellent correlation between the blood flow estimates made with (62)Cu-ETS and (15)O-water for normal tissues (muscle, thyroid, myocardium) and malignant lesions (pulmonary nodules, bone lesions); the regression line was y = 0.85x + 0.15, R(2) = 0.83, for the 88 regions analyzed. Conclusion: (62)Cu-ETS provided high-quality whole-body PET/CT images, and (62)Cu-ETS measures of blood flow were highly and linearly correlated with (15)O-water-derived K1 values (mL(-1) ⋅ min(-1) ⋅ g). This tracer is suitable for use as a PET tracer of tumor perfusion in patients with metastatic renal cell carcinoma.