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1.
Clin Cancer Res ; 15(9): 3177-83, 2009 May 01.
Article in English | MEDLINE | ID: mdl-19383817

ABSTRACT

PURPOSE: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro. EXPERIMENTAL DESIGN: In this phase I, open-label study, patients with advanced solid malignancies were treated with escalating doses of MG98 administered as a continuous i.v. infusion over 7 days repeated every 14 days. Cohorts of three patients, which could be expanded to six patients, were studied. The maximum tolerated dose was defined as the highest dose at which no more than 33% of subjects experienced dose-limiting toxicity. Pharmacokinetic and pharmacodynamic parameters of MG98 were also characterized. RESULTS: Thirty-three patients were treated at doses of 100 to 250 mg/m(2)/d MG98. MG98 was well tolerated with mild fatigue and myalgia, dose-limiting toxicity was asymptomatic transaminitis, and the maximum tolerated dose was 200 mg/m(2)/d. One patient achieved a partial response and another prolonged disease stabilization. Plasma half-life of MG98 was short (2 hours), drug concentrations reaching a dose-dependent steady state during infusion with a volume of distribution equivalent to plasma volume. Suppression of DNMT1 expression was observed in 26 of 32 patients studied. CONCLUSIONS: MG98 was well tolerated with early evidence of clinical activity. Proof of mechanism was observed and measurement of DNMT1 expression in peripheral blood mononuclear cells may be useful in future phase II development.


Subject(s)
Antineoplastic Agents/administration & dosage , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , Enzyme Inhibitors/administration & dosage , Neoplasms/drug therapy , Oligodeoxyribonucleotides/administration & dosage , Thionucleotides/administration & dosage , Adult , Aged , Cohort Studies , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Neoplasms/genetics , Neoplasms/pathology , Oligodeoxyribonucleotides/pharmacokinetics , Prognosis , Thionucleotides/pharmacokinetics , Tissue Distribution , Treatment Outcome
2.
Clin Cancer Res ; 14(8): 2444-9, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18413836

ABSTRACT

PURPOSE: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML. EXPERIMENTAL DESIGN: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which > or =50% of patients experienced >50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days). RESULTS: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients. CONCLUSIONS: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Myelodysplastic Syndromes/drug therapy , Oligodeoxyribonucleotides/therapeutic use , Thionucleotides/therapeutic use , Aged , Aged, 80 and over , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/genetics , Female , Humans , Male , Middle Aged , Oligodeoxyribonucleotides/adverse effects , Oligodeoxyribonucleotides/pharmacokinetics , RNA, Messenger/analysis , Thionucleotides/adverse effects , Thionucleotides/pharmacokinetics
3.
J Clin Oncol ; 26(12): 1940-7, 2008 Apr 20.
Article in English | MEDLINE | ID: mdl-18421048

ABSTRACT

PURPOSE: MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies. PATIENTS AND METHODS: A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs. RESULTS: Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103. CONCLUSION: At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.


Subject(s)
Benzamides/administration & dosage , Benzamides/adverse effects , Neoplasms/drug therapy , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Acetylation/drug effects , Administration, Oral , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzamides/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Histone Deacetylase Inhibitors , Histones/blood , Humans , Leukocytes/drug effects , Leukocytes/metabolism , Male , Middle Aged , Neoplasms/blood , Neoplasms/enzymology , Neoplasms/metabolism , Patient Compliance , Pyrimidines/pharmacokinetics
4.
Invest New Drugs ; 24(2): 159-67, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16502349

ABSTRACT

DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Oligodeoxyribonucleotides/therapeutic use , Repressor Proteins/antagonists & inhibitors , Thionucleotides/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/metabolism , Canada , Carcinoma, Renal Cell/enzymology , Carcinoma, Renal Cell/secondary , Female , Humans , Kidney Neoplasms/enzymology , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Oligodeoxyribonucleotides/adverse effects , Oligodeoxyribonucleotides/metabolism , RNA, Messenger/blood , Thionucleotides/adverse effects , Thionucleotides/metabolism
5.
Invest New Drugs ; 21(1): 85-97, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12795533

ABSTRACT

PURPOSE: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. PATIENTS AND METHODS: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. RESULTS: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. CONCLUSIONS: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , Neoplasms/drug therapy , Oligodeoxyribonucleotides/pharmacology , Oligonucleotides, Antisense/pharmacology , Adult , Aged , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/blood , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fetal Hemoglobin/analysis , Humans , Infusions, Intravenous , Intracellular Signaling Peptides and Proteins , Male , Maximum Tolerated Dose , Middle Aged , Oligodeoxyribonucleotides/administration & dosage , Oligodeoxyribonucleotides/blood , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides, Antisense/blood , Proteins/analysis , Proteins/genetics , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/blood , Thionucleotides , Time Factors , Treatment Outcome , Up-Regulation , Vimentin/blood , Vimentin/genetics , GADD45 Proteins
6.
Curr Opin Mol Ther ; 4(2): 130-7, 2002 Apr.
Article in English | MEDLINE | ID: mdl-12044034

ABSTRACT

A common event in the development of human neoplasia is the loss of growth regulatory tumor suppressor functions. Methylation of 5'-CpG islands of tumor suppressor genes and elevated levels of the DNA-(cytosine-5)-methyltransferase enzymes (DNMT1, 3A and 3B) are also prevalent features of human neoplasia. However, direct evidence that elevated DNMT enzyme levels alter gene expression and influence oncogenesis has been difficult to obtain due to the lack of specific DNMT inhibitors. We have developed potent and selective antisense inhibitors of the known DNA methyltransferases. MG-98, a second-generation DNMT1-specific antisense inhibitor currently in phase II clinical trials, reactivates silenced tumor suppressor genes and inhibits the growth of cancer cells in vitro and in preclinical in vivo models. Here, we will review the discovery and development of MG-98 as a cancer therapeutic.


Subject(s)
DNA Modification Methylases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Clinical Trials as Topic , DNA Modification Methylases/chemistry , DNA Modification Methylases/metabolism , Genes, Tumor Suppressor , Humans , Neoplasms/enzymology , Neoplasms/genetics , Sequence Deletion , Substrate Specificity
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