Burgess B. Freeman

Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. PATIENTS AND METHODS Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. RESULTS There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. CONCLUSION Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased survival of mice bearing cortical implants of mouse and human G3 MBs that overexpress MYC compared to each agent alone, while having little effect on mouse MBs of the sonic hedgehog subgroup. Our findings strongly suggest that combination therapy with pemetrexed and gemcitabine is a promising treatment for G3 MBs.

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high-risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here, we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest, and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

Targeting the DNA Repair Pathway in Ewing Sarcoma

Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or temozolomide. We developed an orthotopic EWS mouse model and performed pharmacokinetic and pharmacodynamic studies using three different PARPis that are in clinical development for pediatric cancer. Irinotecan administered on a low-dose, protracted schedule previously optimized for pediatric patients was an effective DNA-damaging agent when combined with PARPis; it was also better tolerated than combinations with temozolomide. Combining PARPis with irinotecan and temozolomide gave complete and durable responses in more than 80% of the mice.

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.

An open‐label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT).

Evaluation of Gefitinib for Treatment of Refractory Solid Tumors and Central Nervous System Malignancies in Pediatric Patients

Gefitinib (ZD1839, Iressa), a member of the 4-anilinoquinazoline class of compounds, has the chemical name 4-quinazolinamine, N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. Gefitinib often is referred to as a “specific” or “selective” inhibitor of epidermal growth factor receptor (EGFR). EGFR expression has been noted in neuroblastoma and rhabdomyosarcoma cell lines and in tumor specimens from children with Wilms tumor, osteosarcoma, and glioma. Thus, gefitinib, the first marketed EGFR tyrosine kinase inhibitor, was chosen for study in children with refractory solid tumors and central nervous system (CNS) malignancies. This review discusses findings from 3 clinical trials of gefitinib in children with refractory solid tumors and CNS malignancies, focusing on the clinical pharmacology of the compound. To date, gefitinib has been studied in children as a single agent and in combination with irinotecan. Overall, the compound has been well tolerated in children and has a safety profile similar to that observed in adults. The clinical pharmacokinetics of gefitinib in children are similar to those observed in adults. Finally, the future for the use of gefitinib in pediatrics is similar to that of other molecularly targeted agents and awaits definition of tumors and patient populations in which it will be most advantageous.

Optimization of Antitumor Modulators of Pre-mRNA Splicing

The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously, natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1). We report the optimization of a class of tumor-selective spliceosome modulators that demonstrate significant in vivo antitumor activity. This optimization culminated in the discovery of sudemycin D6, which shows potent cytotoxic activity in the melanoma line SK-MEL-2 (IC50 = 39 nM) and other tumor cell lines, including JeKo-1 (IC50 = 22 nM), HeLa (IC50 = 50 nM), and SK-N-AS (IC50 = 81 nM). We also report improved processes for the synthesis of these compounds. Our work supports the idea that sudemycin D6 is worthy of further investigation as a novel preclinical anticancer agent with application in the treatment of numerous human cancers.

Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors

PURPOSE To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]). RESULTS Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed. CONCLUSION The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.

Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

Purpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results: Bevacizumab concentration–time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05). Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res; 20(10); 2783–92. ©2014 AACR.

Combining Quinupristin/Dalfopristin with Other Agents for Resistant Infections

OBJECTIVE To review the resistance mechanisms of Enterococcus and Staphylococcus spp. and summarize quinupristin/dalfopristins (QDs) effects on these resistant organisms when combined with other antibiotics via review of the literature and unpublished data. DATA SOURCES Data were identified by a PubMed search (1996—May 2003) using the search terms quinupristin/dalfopristin, synergy, in vitro, in vivo, vancomycin-resistant Enterococcus faecium (VREF), methicillin-resistant Staphylococcus aureus (MRSA), and individual antibiotic names. Bibliographies of the resultant PubMed searches were reviewed and included if applicable. STUDY SELECTION AND DATA EXTRACTION All studies reviewed were analyzed; specific drug data were included only if clinically pertinent. In vitro data from studies with adequate design were discussed, whereas all case reports and clinical trials were utilized. DATA SYNTHESIS In the treatment of VREF, available information seems conflicting, although some clear differences have become apparent. QD—ampicillin and QD—doxycycline combinations have demonstrated beneficial activity, usually displaying synergistic or additive effects even in macrolide-, lincosamine-, and streptogramin-resistant (MLSB) isolates. Vancomycin and chloramphenicol have shown some efficacy, but antagonistic or null results also have been observed. Regarding MRSA, results from many studies of QD combinations have been ambiguous. More common combinations displayed synergy or additive effects against MRSA, but only QD—rifampin showed consistent beneficial activity against MRSA and MLSB isolates. Most other combinations displayed antagonism when tested in vitro. CONCLUSIONS Data supporting the use of various QD—antibiotic combinations against VREF and MRSA are increasing, but further in vitro and in vivo data are needed to confirm the findings.