Showing papers by "Joel M. Reid published in 2007"
TL;DR: The vitreous half-life of 1.25 mg intravitreal bevacizumab (Avastin) is 4.32 days in a rabbit eye, compared with 4.88 days and 6.86 days for the aqueous and serum values, respectively.
673 citations
TL;DR: Although vitreous concentrations of ranibizumab declined in a monoexponential fashion with a half-life of 2.88 days, concentrations of >0.1 microg/ml ranibzumab were maintained in the Vitreous humor for 29 days, whereas small amounts of intravitreal bevacizumAB have been detected in the serum and fellow uninjected eye.
493 citations
TL;DR: The safe starting dose of MV‐NIS for the clinical protocol was set at 1−2 × 104 TCID50/kg (106 TCID50 per patient), more so after pretreatment with cyclophosphamide.
Abstract: MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 x 10(6) TCID50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10(8) and 4 x 10(8) TCID50/kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1-2 x 10(4) TCID50/kg (10(6) TCID50 per patient).
121 citations
TL;DR: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT and non-DMSO–containing formulations may improve acceptance of this drug by children and their families.
Abstract: Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m 2 /dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m 2 /dose, the C max and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m 2 dose level. Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m 2 /d. Non-DMSO–containing formulations may improve acceptance of this drug by children and their families.
75 citations
TL;DR: The CSF penetration of pemetrexed was less than 2%, suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.
Abstract: Pemetrexed, a multi-targeted antifolate that disrupts synthesis of both purines and pyrimidines, is approved for use in malignant pleural mesothelioma and non-small cell lung cancer. Pemetrexed is currently being evaluated for anti-tumor activity in a variety of solid and central nervous system tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of pemetrexed in a non-human primate model that is highly predictive of human CSF penetration. Pemetrexed, 20 mg/kg (400 mg/m2), was administered intravenously to four non-human primates. Serial blood samples were obtained from all animals and serial CSF samples were obtained from three animals. Plasma and CSF concentrations of pemetrexed were measured using LC/MS/MS and the resulting concentration versus time data were evaluated using model independent and dependent methods. Pemetrexed disappearance from plasma was best described by a two compartment model with a mean distribution half-life of 13.8 ± 3.2 min and an elimination half-life of 70.0 ± 16.0 min. The volume of distribution of and the clearance from the central compartment were 0.066 ± 0.017 l/kg and 3.6 ± 0.6 ml/min/kg, respectively. Peak CSF concentrations occurred 40–71 min after the start of the infusion with an average of 0.26 ± 0.15 μM. The CSF penetration of pemetrexed was less than 2% (range 0.33–1.58%), suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.
35 citations
TL;DR: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults, and the recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.
Abstract: Purpose We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients ...
23 citations
TL;DR: Recurrent GBM patients having received = 1 prior chemo regimen for progressive disease were eligible and Vorinostat dose was 200 mg bid x 14 days q 3 weeks.
Abstract: 2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen fo...
15 citations
TL;DR: V is an oral inhibitor of histone deacetylase that inhibits growth of glioblastoma cell lines and has supra-additive activity when combined with TMZ, and a phase I study of V in combination with TMZ in patients with malignant gliomas is conducted.
Abstract: 2039 Background: Vorinostat (V) is an oral inhibitor of histone deacetylase. In preclinical studies it inhibits growth of glioblastoma (GBM) cell lines and has supra-additive activity when combined with TMZ. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria are histologically proven GBM and anaplastic gliomas (AG) who have received radiotherapy and have not progressed on temozolomide, > 18 yrs old, life expectancy > 8 weeks, KPS > 60, adequate bone marrow reserve and organ function. There was no limitation to the type of antiepileptic drugs that could be used. All patients received TMZ at a dose of 150 mg/m2/day on days 1–5 days every 28 days. Variable doses of V were administered with food on days 1–14 every 28 days. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopen...
6 citations
TL;DR: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD) and assessments of toxicity were performed with each cycle.
Abstract: 3598 Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu) 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD) Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (24 - 40 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB) Assessments of toxicity were performed with each cycle and clinical response was deter
2 citations
TL;DR: A simple limited sampling model for AUC of 17-AAG and its active metabolite, 17-(amino)-17-demethoxygeldanomycin (17-AG) using drug concentrations from a few time points is developed using a multivariate linear regression and bootstrap resampling approach.
Abstract: The Hsp90-directed anticancer agent 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) is currently undergoing phase I and phase II clinical investigation. Our goal was to develop a simple limited sampling model (LSM) for AUC of 17-AAG and its active metabolite, 17-(amino)-17-demethoxygeldanomycin (17-AG) using drug concentrations from a few time points. Pharmacokinetic data from 34 patients treated at 11 dose levels on a Mayo Clinic Cancer Center phase I clinical trial of 17-AAG was utilized. Blood samples were collected at 11 different time points, spanning 25 h. Graphical methods and correlations were used to assess functional forms and univariate relationships. Multivariate linear regression and bootstrap resampling were used to develop the LSM. Using log-transformed data, the two and three time point 17-AAG LSMs are log-AUC (17-AAG) = 0.869 + 0.653*(C55min) +0.469*(C5h) and log-AUC (17-AAG) = 2.449 + 0.400*(C55min) +0.441*(C5h) +0.142*(C9h). The two and three time point LSMs for 17-AG are log-AUC (17-AG) = 3.590 + 0.747*(C5h) +0.169*(C17h), and log-AUC (17-AG) = 3.797 + 0.650*(C5h) +0.111*(C9h) +0.122*(C17h). Ninety-seven percent and 94% of the predicted log-AUC values were within 5% of the observed log-AUC for the two and three time point models for 17-AAG and 17-AG respectively. The precise calculation of AUC is cumbersome and expensive in terms of patient and clinical resources. The LSM developed using a multivariate regression approach is clinically and statistically meaningful. Prospective validation is underway.
2 citations
TL;DR: The maximum tolerated dose (MTD) of orally administered IRN is determined when given with fixed- dose TEM and VCR in children with relapsed or refractory solid tumors, using the antibiotic cefixime to reduce IRN-associated diarrhea.
Abstract: 9563 Background: Both temozolomide (TEM) and vincristine (VCR) can increase the preclinical activity of low-dose protracted irinotecan (IRN) against pediatric solid tumors. Because these drugs have...