Safety and Efficacy of PF-3512676 for the Treatment of Stage IV Renal Cell Carcinoma: An Open-Label, Multicenter Phase I/II Study Journal Article

Authors: Thompson, J. A.; Kuzel, T.; Drucker, B. J.; Urba, W.; Bukowski, R.
Article Title: Safety and Efficacy of PF-3512676 for the Treatment of Stage IV Renal Cell Carcinoma: An Open-Label, Multicenter Phase I/II Study
Abstract: Purpose: Single-agent PF-3512676 (agatolimod), a Toll-like receptor 9 agonist, was examined in an open-label, single-arm, multicenter phase I/II study to determine its maximum tolerated dose (MTD), safety profile, antitumor activity, pharmacokinetics, and immunologic effects in patients with advanced metastatic renal cell carcinoma (RCC). Patients and Methods: PF-3512676 was administered subcutaneously weekly for up to 24 weeks to 39 adults with stage IV RCC. Patients were excluded if they had received previous therapy other than surgery. Phase I dose escalation began at 0.08 mg/kg, with phase II expansion to 20 patients to estimate objective response rates at 0.16 mg/kg. Doses were subsequently escalated to 0.81 mg/kg according to the phase I design. Results: An MTD was not reached. One patient who received 0.54 mg/kg had dose-limiting toxicities (grade 3 nonhematologic adverse events [AEs], including anorexia). The most commonly reported AEs were flu-like symptoms and local injection-site reactions of mild-to-moderate severity. The most commonly reported serious AE was grade 3 fatigue in 4 patients (10%). Grade 4 AEs included anemia, exacerbated dyspnea, and polyarthralgia in 1 patient each. Two patients (5%), 1 each in the 0.16-mg/kg and 0.54-mg/kg cohorts, achieved a partial response. Both responses were durable (35 and 40 months). Conclusion: This was the first study to examine PF-3512676 safety and antitumor activity in patients with advanced RCC. Single-agent treatment was tolerable. At the doses tested, PF-3512676 had modest antitumor activity. Additional studies in combination with other agents or at higher monotherapy doses might be warranted.
Keywords: adult; clinical article; treatment outcome; aged; middle aged; clinical trial; fatigue; neutropenia; advanced cancer; area under the curve; cancer growth; drug efficacy; drug safety; drug withdrawal; hypophosphatemia; treatment duration; antineoplastic agents; alpha interferon; chemotherapy, adjuvant; neoplasm staging; anorexia; phase 2 clinical trial; anemia; tumor volume; leukopenia; nausea; thrombocytopenia; myalgia; antineoplastic activity; kidney carcinoma; kidney neoplasms; risk assessment; arthralgia; chill; drug dose escalation; drug fever; dyspnea; injection site reaction; lymphocytopenia; chemotherapy induced emesis; confusion; drug fatality; hypotension; malaise; lung metastasis; disease severity; rigor; immunotherapy; carcinoma, renal cell; multicenter study; agatolimod; drug response; interleukin 6; flu like syndrome; weakness; maximum plasma concentration; time to maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; memory disorder; gamma interferon inducible protein 10; muscle spasm; monocyte chemotactic protein 1; soft tissue metastasis; inducible protein-10; toll-like receptor 9; interleukin 12p40; oligodeoxyribonucleotides
Journal Title: Clinical Genitourinary Cancer
Volume: 7
Issue: 3
ISSN: 1558-7673
Publisher: Elsevier Inc.  
Date Published: 2009-10-01
Start Page: E58
End Page: E65
Language: English
DOI: 10.3816/CGC.2009.n.025
PUBMED: 19815483
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "Source: Scopus"
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