This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.
Purpose Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)–naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1–naïve advanced melanoma. Patients and Methods PEG-IFN (1, 2, and 3 μg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival. Results Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%. Conclusion Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1–naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.
3047 Background: Apo2L/TRAIL (Apo2L ligand/tumor necrosis factor-related apoptosis-inducing ligand) is the first recombinant human protein that selectively induces apoptosis or programmed cell death in cancer cells while sparing normal cells. The molecule used in this joint clinical development between Genentech, Inc. and Amgen, Inc., is an optimized recombinant human Apo2L/TRAIL protein produced in E. coli. It displays broad activity in preclinical models of a variety of solid and hematologic cancers. This is the first report of the pharmacokinetics of Apo2L/TRAIL in humans. Methods: Thirty-nine patients enrolled in a phase 1a study had PK assessments at dose levels ranging from 0.5–15 mg/kg in two cohorts, those with and those without liver metastases. Recombinant human Apo2L/TRAIL was administered as a 1-hr IV infusion for 5 consecutive days over a 21-day cycle. Serum concentrations were determined using a sensitive ELISA assay. PK calculations were performed using Non-compartmental analyses. Results: Currently Apo2L/TRAIL PK data are available for 27 patients, 15 in cohort 1 (no liver metastases) and 12 in cohort 2 (liver metastases). Mean (± SD) PK data for patients in cohort 1 and cohort 2 did not differ. PK data for cohort 1 are outlined in the table below. Apo2L/TRAIL clearance appeared proportional to dose and consistent with that predicted from nonclinical models. Cmax achieved at doses ≥ 4 mg/kg are equivalent to or greater than those displaying activity in preclinical models. There was no evidence of drug accumulation between day 1 and day 5 of treatment. Conclusions: Apo2L/TRAIL at doses which can be safely administered in humans produces serum concentrations consistent with those demonstrating efficacy in tumor xenograft models. Hepatic metastases with or without mild liver dysfunction do not appear to influence the PK of Apo2L/TRAIL. [Table: see text] [Table: see text]
Rhabdoid tumor of the kidney is an uncommon and highly aggressive malignancy usually found in the pediatric age group. This tumor does not respond well to aggressive chemotherapy regimens and survival tends to be short. Only two cases of rhabdoid tumor of the kidney occurring in adults have been described previously. The third case of a rhabdoid tumor of the kidney in an adult is presented here. This clinical case report is unique not only because of the rare occurrence of this tumor in adulthood but because the patient described had an objective antitumor response to outpatient low dose interleukin-2. This single case report may have therapeutic implications for other patients with this tumor.
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