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ABSTRACT: The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates.
A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25-105 mg/m(2) IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system.
3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study.
This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.
Cancer Chemotherapy and Pharmacology 05/2010; 67(2):393-400. · 2.83 Impact Factor
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ABSTRACT: To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors.
The combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m².
Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days).
The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.
Investigational New Drugs 12/2009; 29(2):316-22. · 3.36 Impact Factor
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ABSTRACT: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of MN-209, a novel vascular disrupting agent, in patients with advanced solid tumors.
MN-029 was administered weekly for three consecutive weeks out of four; two cycles were planned. Dose escalation proceeded by 100% per toxicity criteria. Intra-patient dose escalation was permitted.
Twenty patients received a total of 151 infusions of MN-029. No DLTs or grade 4 toxicities occurred. The most common adverse events were nausea, vomiting, arthralgias, and headache. One patient developed acute substernal chest pain 4 days after his first dose of MN-029 and was removed from the study. An MTD was not determined. The recommended phase II dose was identified as 180 mg/m(2)/week. One patient with advanced pancreatic cancer attained a partial response lasting 10 weeks.
MN-029 was well tolerated in this schedule. Further development of this class of agents is warranted, especially in combination with other anti-cancer treatments.
Investigational New Drugs 06/2009; 28(4):509-15. · 3.36 Impact Factor
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ABSTRACT: The objective of ECOG 1503 was to determine the response rate of this combination in the second-line treatment of advanced NSCLC.
Triapine 105 mg/m(2) IV on days 1, 8, and 15, and gemcitabine 1,000 mg/m(2) on days 1, 8, and 15, of a 28 day cycle.
Eighteen patients enrolled. Three patients were not eligible due to protocol violations. No objective antitumor responses were seen. Three patients (20%) experienced stable disease (90% CI 5.7-44%). Median overall survival: 5.4 months (95% CI 4.2-11.6 months); median time to progression: 1.8 months (95% CI 1.7-3.5 months). Five patients developed acute infusion reactions to Triapine related to elevated methemoglobinemia. Patients with MDR1 variant genotypes of C3435T experienced superior overall survival compared to non-variants (13.3 vs. 4.3 months, respectively, p = 0.023).
This regimen did not demonstrate activity in relapsed NSCLC. Prolonged survival seen with MDR1 variant genotypes is hypothesis-generating.
Investigational New Drugs 03/2009; 28(1):91-7. · 3.36 Impact Factor
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William R Schelman,
Sherry Morgan-Meadows,
Rebecca Marnocha,
Fred Lee,
Jens Eickhoff,
Wei Huang,
Marcia Pomplun,
Zhisheng Jiang,
Dona Alberti,
Jill M Kolesar,
Percy Ivy,
George Wilding, Anne M Traynor
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ABSTRACT: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin.
Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment.
Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer.
Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.
Cancer Chemotherapy and Pharmacology 01/2009; 63(6):1147-56. · 2.83 Impact Factor
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Jill Kolesar,
Wei Huang,
Jens Eickhoff,
Kristine Hahn,
Dona Alberti,
Steven Attia,
William Schelman,
Kyle Holen, Anne Traynor,
Percy Ivy,
George Wilding
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ABSTRACT: The purpose of this study was to evaluate baseline RRM2 protein and gene expression in tumors of patients receiving 3-AP.
Tumor blocks from patients enrolled in phase I and II clinical studies using 3-AP, were evaluated for RRM2 gene and protein expression by quantitative real time polymerase chain reaction (Q-RTPCR) and automated quantitative analysis (AQUA).
Esophageal and gastric cancers overexpressed RRM2 protein when compared to prostate cancer (Z-score, 0.68 +/- 0.94 SD, vs 0.41 +/- 0.84 SD, respectively; p = 0.04). Esophageal and gastric cancers also overexpressed RRM2 mRNA when compared to prostate cancer (relative gene expression 2.56 +/- 1.49 SD, vs 0.29 +/- 0.20 SD, respectively; p = 0.02). Protein and gene expression were moderately associated (Spearman's rank correlation = 0.30; p = 0.12).
RRM2 gene and protein expression varies by tumor type.
Cancer Chemotherapy and Pharmacology 11/2008; 64(1):79-86. · 2.83 Impact Factor
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Steven Attia,
Sherry Morgan-Meadows,
Kyle D Holen,
Howard H Bailey,
Jens C Eickhoff,
William R Schelman, Anne M Traynor,
Daniel L Mulkerin,
Toby C Campbell,
Thomas A McFarland,
Michael S Huie,
James F Cleary,
Amye J Tevaarwerk,
Dona B Alberti,
George Wilding,
Glenn Liu
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ABSTRACT: To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine.
Eligible adults (advanced solid tumor; performance status <or=2) received capecitabine 500 mg/m(2) PO BID days 1-14 and FDR gemcitabine (400-1,000 mg/m(2) escalated by 200 mg/m(2) increments) at 10 mg/m(2)/min days 1 and 8 on a 21-day cycle. A traditional 3 + 3 cohort design was used to determine the MTD.
Thirty patients (median age 59 years) were enrolled. The predominant grade >or=3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m(2) gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia >or=7 days). At dose level 3 (800 mg/m(2) gemcitabine), one patient had a DLT (grade 3 neutropenia >or=7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m(2) PO BID days 1-14 with 800 mg/m(2) FDR gemcitabine days 1 and 8 infused at 10 mg/m(2) per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas.
This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas.
Cancer Chemotherapy and Pharmacology 10/2008; 64(1):45-51. · 2.83 Impact Factor
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Glenn Liu,
Jill Kolesar,
Douglas G McNeel,
Catherine Leith,
Kathy Schell,
Jens Eickhoff,
Fred Lee, Anne Traynor,
Rebecca Marnocha,
Dona Alberti,
James Zwiebel,
George Wilding
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ABSTRACT: This phase I trial assessed the safety and tolerability of G3139 when given in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined.
Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1-7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (prechemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured.
Forty-two patients were evaluable for safety analysis. Primary toxicities were hematologic (myelosuppression and thrombocytopenia). Dose escalation was stopped with G3139 at 7 mg/kg/d, carboplatin at area under the curve of 6, and paclitaxel at 175 mg/m(2) due to significant neutropenia seen in cycle 1 and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/d, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs.
Although the maximal tolerated dose was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs.
Clinical Cancer Research 06/2008; 14(9):2732-9. · 7.74 Impact Factor
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ABSTRACT: We report on the technical feasibility, dosimetric aspects, and daily image-guidance capability with megavoltage CT (MVCT) of stereotactic body radiotherapy (SBRT) using helical tomotherapy for medically inoperable T1/2 N0 M0 non-small cell lung cancer. Nine patients underwent treatment planning with 4D-CT in a double vacuum based immobilization system to minimize tumor motion and to define a lesion-specific 4D-motion envelope. Patients received 60 Gy in 5 fractions within 10 days to a PTV defined by a motion envelope plus a 6 mm expansion for microscopic extension and setup error using tomotherapy, with daily pretreatment MVCT image guidance. The primary endpoint was technical feasibility. Secondary endpoints were defining the acute and sub-acute toxicities and tumor response. Forty three of 45 fractions were successfully delivered, with an average delivery time of 22 minutes. MVCT provided excellent tumor visualization for daily image guidance. No significant tumor regression was observed on MVCT in any patient during therapy. Median mean normalized total doses were: tumor 117 Gy10; residual lung 9 Gy3. Maximum fraction-size equivalent dose values were: esophagus 5 Gy39; cord 7 Gy36. No patient experienced > or = grade 2 pulmonary toxicity. 3 complete, 4 partial and 2 stable responses were observed, with <3 months median follow-up. The mean tumor regression is 72%. SBRT using tomotherapy proved to be feasible, safe and free of major technical limitations or acute toxicities. Daily pretreatment MVCT imaging allows for precise daily tumor targeting with the patient in the actual treatment position, and therefore provides for precise image guidance.
Acta Oncologica 02/2006; 45(7):890-6. · 3.33 Impact Factor
