Phase I trial of the single-chain urokinase intrapleural LTI-01 in complicated parapneumonic effusions or empyema
Lutz Beckert, Ben Brockway, Graham Simpson, Anne Marie Southcott, Y.C. Gary Lee, Najib Rahman, Richard W. Light, Steven Shoemaker, John Gillies, Andrey A. Komissarov, Galina Florova, Timothy Ochran, William Bradley, Harrison Ndetan, Karan P. Singh, Krishna Sarva, Steven Idell
Lutz Beckert, Ben Brockway, Graham Simpson, Anne Marie Southcott, Y.C. Gary Lee, Najib Rahman, Richard W. Light, Steven Shoemaker, John Gillies, Andrey A. Komissarov, Galina Florova, Timothy Ochran, William Bradley, Harrison Ndetan, Karan P. Singh, Krishna Sarva, Steven Idell
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Clinical Research and Public Health Clinical trials

Phase I trial of the single-chain urokinase intrapleural LTI-01 in complicated parapneumonic effusions or empyema

Abstract

BACKGROUND. Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE)/empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (a single-chain urokinase [scuPA]), which is relatively resistant to plasminogen activator inhibitor–1 (PAI-1), would be well tolerated.METHODS. This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy.RESULTS. LTI-01 was well tolerated, with no bleeding, treatment-emergent adverse events, or surgical referrals (n = 14 subjects). Urokinase PA (uPA) antigen increased in PFs at 3 hours after LTI-01 (P < 0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1–resistant bioactive complexes, and increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis or increments in plasma D-dimers. Decreased pleural opacities occurred in all but 1 subject. Both subjects receiving 800,000 IU required 2 doses to relieve pleural sepsis, with 2 other subjects similarly responding at lower doses.CONCLUSION. LTI-01 IPFT was well tolerated at these doses, with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs, where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed.TRIAL REGISTRATION. ANZCT ID: ACTRN12616001442493.FUNDING. Lung Therapeutics Inc. (LTI), NIH SMARTT HHSN268201100014C (SI), UO-1 HL121841-01A1 (SI). 1R01HL130402-01A1 (AAK, GF, SI), UTHSCT AG18-09 (AAK).

Authors

Lutz Beckert, Ben Brockway, Graham Simpson, Anne Marie Southcott, Y.C. Gary Lee, Najib Rahman, Richard W. Light, Steven Shoemaker, John Gillies, Andrey A. Komissarov, Galina Florova, Timothy Ochran, William Bradley, Harrison Ndetan, Karan P. Singh, Krishna Sarva, Steven Idell

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Figure 2

Biochemical responses to LTI-01 IPFT in pleural fluid and plasma.

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Biochemical responses to LTI-01 IPFT in pleural fluid and plasma. Succes...
Successful delivery of LTI-01 to the pleural space (A) coincided with an increase in plasminogen activating (PA) (B) and fibrinolytic (C) activities and level of fibrin degradation product (D-dimers) (D) in pleural fluid at 3 hours after treatment, and did not affect levels of uPA antigen (E) or D-dimers in plasma (F). LTI-01 was delivered daily at doses of 50,000 (pink symbols; n = 3), 100,000 (blue symbols; n = 3), 200,000 (orange symbols; n = 3), 400,000 (purple symbols; n = 3), and 800,000 (green symbols; n = 2) IU per injection. Samples of pleural fluid (day 1 before treatment [pre] n = 12, day 1 after treatment [post] n = 14, day 2 pre-treatment n = 9, day 2 post-treatment n = 13, day 3 pre-treatment n = 2, day 3 post-treatment n = 8, and day 4 n = 4) and plasma (day 1 and pre–day 3 treatment n = 14 each, day 3 post-treatment n = 5, and day 4 n = 5) were collected daily (1–4 days) just prior to each LTI-01 injection (pre) and 3 hours after (post) treatment as described in Methods. Levels of urokinase antigen were determined in pleural fluid (A) and plasma (E) using ELISA analyses (R&D Systems). Plasminogen activating (PA) activity in pleural fluid (B) was determined by measuring the rates of activation of exogenously added human Glu-pasminogen (200 nM) and fluorogenic plasmin substrate (200 μM) SN-5 (HTI) as previously described (21). The fibrinolytic activity in pleural fluid (C) was measured by FITC-fibrin assay, as described elsewhere (21). D-dimers were determined in pleural fluid (D) and plasma (F) using ELISA (Abcam). The plasma samples collected from the patient diagnosed with metastatic squamous cell carcinoma were excluded from the analysis. Each point represents the average of at least 2 independent measurements. Data are presented as dot plots, with horizontal lines indicating the medians and whiskers representing interquartile range. *P < 0.05, **P < 0.001, ***P < 0.0001, NS: P ≥ 0.05, Wilcoxon’s matched-pairs signed-rank test (assessed at the 5% level of significance). Dashed line indicates the lowest limit of detection (LOD) of the method.