Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC)

Abstract

4644 Background: Patients with metastatic RCC have a poor prognosis, with infrequent responses to immunotherapy. CPG 7909, one of a new class of oligodeoxynucleotide immunomodulators, binds Toll-like receptor 9 on dendritic cells, with induction of cytokines including IFNα, activation of NK cells, and modulation of a Th1 CTL environment. Early trials of CPG 7909 demonstrated anti-tumor activity in human cancers at well-tolerated doses. Based upon the medical need and the novel mechanism of action, the current trial evaluates CPG 7909 in the treatment of metastatic RCC. Methods: This multi-center, dose escalation trial evaluates weekly s.c. doses of CPG 7909 with cohorts of patients given 0.08, 0.12, 0.16, 0.36, 0.54 or 0.81 mg/kg for 24 weeks or until progression. Patients had prior nephrectomy but no systemic therapy for clear-cell RCC, ECOG performance ≤1, with measurable soft tissue metastases (bone, liver, brain excluded). The primary endpoint is safety, with secondary endpoints including pharmacokinetic and pharmacodynamic parameters, responses by RECIST, duration of response, time to progression, and survival. Results: Thirty-one patients have enrolled, 18 males and 13 females, ages 35–79. Twenty-seven patients are off-study prior to, or at 24 weeks of treatment. One patient had a durable PR (8 months), 9 had stable disease and 17 patients progressed on CPG 7909. Four patients continue on therapy. Median time to progression is 112 days. No drug-related serious adverse events have been reported, with good tolerability up to 0.54 mg/kg. Pro-inflammatory or cytokine effects (erythematous injection-site reactions, chills, myalgias, arthralgias and fatigue) are dose related and reversible. Biologic responses are consistent with the CpG TLR9 mechanism of action; the most consistent effects are increased plasma IP-10 and 2'5 OAS. Conclusions: In this ongoing dose-escalation study, CPG 7909 can be safely administered at doses up to 0.54 mg/kg weekly. Correlations of PK, PD, clinical symptoms and response will be provided. No significant financial relationships to disclose.