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.

• Authors: John A Thompson, Timothy Kuzel, Beverly J Drucker, Walter J Urba, Ronald M Bukowski
• Journal: Clinical genitourinary cancer (Clin Genitourin Cancer) Vol. 7 Issue 3 Pg. E58-65 (Oct 2009) ISSN: 1938-0682 [Electronic] United States
• PMID: 19815483 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Oligodeoxyribonucleotides
• ProMune
• TLR9 protein, human
• Toll-Like Receptor 9

Topics

• Adult
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Chemotherapy, Adjuvant
• Female
• Humans
• Kidney Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Oligodeoxyribonucleotides (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Toll-Like Receptor 9 (agonists)
• Treatment Outcome