Safety and efficacy of PF-3512676 for the treatment of stage IV renal cell carcinoma: an open-label, multicenter phase I/II study.
OBJECTIVE
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).


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).


CONCLUSIONS
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.
Thompson
John A
JA
Division of Medical Oncology, University of Washington, Seattle, WA, USA. jat@u.washington.edu
Kuzel
Timothy
T
Drucker
Beverly J
BJ
Urba
Walter J
WJ
Bukowski
Ronald M
RM
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051217:Toll-Like Receptor 9 / Q000819:agonists; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; C483020:ProMune; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9