Jeffrey W. Sherman

Direct Intracerebral Delivery of Cintredekin Besudotox (IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin Besudotox Intraparenchymal Study Group

PURPOSE Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG). PATIENTS AND METHODS Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion. RESULTS A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 microg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years. CONCLUSION CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.

Convection-enhanced delivery of cintredekin besudotox (interleukin-13- PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: Phase 1 study of final safety results

OBJECTIVECintredekin besudotox (CB), a recombinant cytotoxin consisting of interleukin-13 and truncated Pseudomonas exotoxin, binds selectively to interleukin-13Rα2 receptors overexpressed by malignant gliomas. This study assessed the safety of CB administered by convection-enhanced delivery followed by standard external beam radiation therapy (EBRT) with or without temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) in patients with newly diagnosed malignant gliomas. METHODSAfter gross total resection of the tumor, two to four intraparenchymal catheters were stereotactically placed and CB (0.25 or 0.5 μg/mL) was infused for 96 hours. This was followed, 10 to 14 days later, by EBRT (5940–6100 cGy, 5 d/wk for 6–7 wk) with or without temozolomide (75 mg/m2/d, 7 d/wk during EBRT). Safety was assessed during an 11-week observation period after catheter placement RESULTSTwenty-two patients (12 men, 10 women; median age, 55 yr; 21 with glioblastoma multiforme and one with an anaplastic mixed oligoastrocytoma) were enrolled. None of the patients experienced dose-limiting toxicities in the first two cohorts (0.25 μg/mL CB + EBRT [n = 3] and 0.25 μg/mL CB + EBRT + temozolomide [n = 3]). One patient experienced a dose-limiting toxicity (Grade 4 seizure) in the third cohort (0.5 μg/mL CB + EBRT [n = 6]). Six patients in the final cohort (0.5 μg/mL CB + EBRT + temozolomide [n = 10]) completed treatment, and one patient experienced a dose-limiting toxicity (Grade 3 aphasia and confusion). Four patients were not considered evaluable for a dose decision and were replaced. CB related adverse events occurring in more than one patient were fatigue, gait disturbance, nystagmus, and confusion. No Grade 3 to 4 hematological toxicities were observed. CONCLUSIONCB (0.5 μg/mL) administered via convection-enhanced delivery before standard radiochemotherapy seems to be well tolerated in adults with newly diagnosed malignant gliomas. Further clinical study assessment is warranted.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Neutropenia during Phase I Development of Liposome-Entrapped Paclitaxel

Purpose: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. Experimental Design: LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m2). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. Results: The MTD of LEP-ETU was identified as 325 mg/m2. DLTs occurring at 375 mg/m2 consisted of febrile neutropenia and neuropathy. The Cmax and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 μg/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m2 q3w. For a dose of 110 mg/m2 given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. Conclusions: LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m2 LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m2 Taxol q3w. A 275 mg/m2 dose may offer an improved therapeutic index.

Ceftriaxone treatment of multidrug-resistant salmonella osteomyelitis

Empiric treatment of serious Salmonella infections has been complicated by the emergence of strains resistant to multiple antimicrobial agents, including ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. Recent reports suggest that the third-generation cephalosporins may be effective therapy for Salmonella infections. This report describes a case of antibiotic-resistant Salmonella heidelberg prosthetic hip infection successfully treated with prosthesis removal and once-daily ceftriaxone. Tube dilution sensitivity testing of the organism demonstrated minimal inhibitory and minimal bactericidal concentrations of 0.12 microgram/ml. Serum bactericidal activity, 30 minutes after infusion, was inhibitory and bactericidal at 1:512. It is concluded that the favorable preliminary results reported in the literature and the outcome in this patient suggest that the third-generation cephalosporins may be effective therapy for Salmonella infections and should undergo clinical trials.