Browsing by Author "Puzanov, Igor"

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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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    Augmenting antibody response to EGF-depleting immunotherapy: Findings from a phase I trial of CIMAvax-EGF in combination with nivolumab in advanced stage NSCLC
    (Frontiers Media, 2022-08-03) Evans, Rachel; Lee, Kelvin; Wallace, Paul K.; Reid, Mary; Muhitch, Jason; Dozier, Askia; Mesa, Circe; Luaces, Patricia L.; Santos-Morales, Orestes; Groman, Adrienne; Cedeno, Carlos; Cinquino, Aileen; Fisher, Daniel T.; Puzanov, Igor; Opyrchal, Mateusz; Fountzilas, Christos; Dai, Tong; Ernstoff, Marc; Attwood, Kristopher; Hutson, Alan; Johnson, Candace; Mazorra, Zaima; Saavedra, Danay; Leon, Kalet; Lage, Agustin; Crombet, Tania; Dy, Grace K.; Medicine, School of Medicine
    Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.
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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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    Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer
    (Springer Nature, 2020-11) Voss, Martin H.; Gordon, Michael S.; Mita, Monica; Rini, Brian; Makker, Vicky; Macarulla, Teresa; Smith, David C.; Cervantes, Andrés; Puzanov, Igor; Pili, Roberto; Wang, Ding; Jalal, Shadia; Pant, Shubham; Patel, Manish R.; Neuwirth, Rachel l.; Enke, Aaron; Shou, Yaping; Sedarati, Farhad; Faller, Douglas V.; Burris, Howard A., III; Medicine, School of Medicine
    Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours. Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients). Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers. Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.