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Journal of Thoracic Oncology : Official... Nov 2009We aimed to evaluate the safety and efficacy of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy in patients with locally advanced or... (Comparative Study)
Comparative Study Randomized Controlled Trial
Phase 1-2a multicenter dose-ranging study of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy for patients with advanced non-small cell lung cancer.
INTRODUCTION
We aimed to evaluate the safety and efficacy of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy in patients with locally advanced or metastatic non-small cell lung cancer.
METHODS
This was a phase 1-2a, multicenter, dose-ranging trial that enrolled patients with stage IIIB or IV non-small cell lung cancer with measurable disease. Patients received canfosfamide in doses ranging from 400 to 1000 mg/m2 intravenously (IV) with carboplatin at area under the curve 6 IV and paclitaxel at 200 mg/m2 IV day 1 every 3 weeks. The primary end point was objective response rate, and the secondary endpoints were safety and progression-free survival.
RESULTS
One hundred twenty-nine patients were treated with canfosfamide at dose levels of 400 (n = 3), 500 (n = 51), 750 (n = 54), and 1000 mg/m2 (n = 21). Objective tumor responses by RECIST were observed in 40 patients [34% (95% confidence interval [CI], 26-44)], the median progression-free survival was 4.3 months (95% CI, 3.7-5.2) and the median survival 9.9 months (95% CI, 7.7-11.9). The percent of patients alive at 1 year was 43.1%. The overall safety profile of the combination was acceptable and consistent with the profiles of the individual agents. In an exploratory analysis, patients receiving the optional maintenance canfosfamide therapy had a prolonged median survival of 16.8 months compared with those eligible for but not receiving maintenance therapy at 8.8 months (hazard ratio = 0.38, p < 0.001).
CONCLUSIONS
The combination of canfosfamide with carboplatin and paclitaxel chemotherapy is well tolerated and active. Maintenance canfosfamide may further improve outcomes. This regimen is worthy of additional study.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cytotoxins; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glutathione; Humans; Injections, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Treatment Outcome
PubMed: 19701107
DOI: 10.1097/JTO.0b013e3181b6b84b -
Journal of Hematology & Oncology Mar 2010Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with...
BACKGROUND
Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum resistant ovarian cancer. Patients with platinum resistant ovarian carcinoma and measurable disease received canfosfamide at 960 mg/m2 in combination with PLD at 50 mg/m2, intravenously day 1 in every 28 day cycles until tumor progression or unacceptable toxicities. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS).
RESULTS
Canfosfamide plus PLD combination therapy was administered at 960/50 mg/m2, respectively. Thirty-nine patients received a median number of 4 cycles (range 1.0-18.0). The ORR was 27.8% (95% CI, 14.2-45.2) with a disease stabilization rate of 80.6% (95% CI, 64.0-91.8) in the evaluable population. The CA-125 marker responses correlated with the radiological findings of complete response or partial response. The median PFS was 6.0 months (95% CI, 4.2-7.9) and median survival was 17.8 months. The combination was well tolerated. Myelosuppression was managed with dose reductions and growth factor support. Grade 3 febrile neutropenia was observed in 2 patients (5.1%). Non-hematologic adverse events occurred at the expected frequency and grade for each drug alone, with no unexpected or cumulative toxicities.
CONCLUSIONS
Canfosfamide in combination with PLD is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer. A randomized phase 3 study was conducted based on this supportive phase 2 study.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Female; Glutathione; Humans; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Platinum Compounds; Polyethylene Glycols; Survival Analysis; Treatment Failure
PubMed: 20222977
DOI: 10.1186/1756-8722-3-9 -
Journal of Thoracic Oncology : Official... Sep 2006Cytotoxic agents have unequivocal activity in non-small cell lung cancer. Currently available agents have demonstrated the ability to prolong life and improve quality of... (Review)
Review
Cytotoxic agents have unequivocal activity in non-small cell lung cancer. Currently available agents have demonstrated the ability to prolong life and improve quality of life in advanced disease, and to increase the rate of cure when used in stage I and II disease in the adjuvant setting and as part of chemoradiotherapy in stage III disease. These agents have served as the core regimen to which agents effecting newly discovered molecular targets are added. However, there is little question that there is much room for improvement. A number of new agents have been identified that either derive from older drugs or affect their targets in novel ways. In particular, tubulin has been an attractive target since the dawn of medical oncology. A number of new antitubulin agents are currently in development. Epothilones are novel agents that bind to the same site as taxanes, yet are structurally distinct. Xyotax and abraxane are agents in which paclitaxel is delivered in a novel fashion that may both reduce toxicity and enhance activity. ABT 751 is an agent that targets the colchicine site of tubulin. Another approach is to enhance the activity of currently available agents by targeting detoxification and resistance pathways. TLK-286 is a novel agent that may enhance the activity of previously available agents by inhibiting GST-pi, a detoxifying mechanism that may be of particular relevance to platinum agents. It has also demonstrated some single-agent cytotoxic activity.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cytotoxins; Drug Delivery Systems; Epothilones; Glutathione; Humans; Lung Neoplasms; Taxoids; Tubulin Modulators
PubMed: 17409954
DOI: No ID Found -
Methods in Enzymology 2005Anticancer drug development using the platform of glutathione (GSH), glutathione S-transferases (GST) and pathways that maintain thiol homeostasis has recently produced... (Review)
Review
Anticancer drug development using the platform of glutathione (GSH), glutathione S-transferases (GST) and pathways that maintain thiol homeostasis has recently produced a number of lead compounds. GSTpi is a prevalent protein in many solid tumors and is overexpressed in cancers resistant to drugs. It has proved to be a viable target for pro-drug activation with at least one candidate in late-stage clinical development. In addition, GSTpi possesses noncatalytic ligand-binding properties important in the direct regulation of kinase pathways. This has led to the development and testing of agents that bind to GSTpi and interfere with protein-protein interactions, with the phase II clinical testing of one such drug. Attachment of glutathione to acceptor cysteine residues (glutathionylation) is a posttranslational modification that can alter the structure and function of proteins. Two agents in preclinical development (PABA/NO, releasing nitric oxide on GST activation, and NOV-002, a pharmacologically stabilized pharmaceutical form of GSSG) can lead to glutathionylation of a number of cellular proteins. The biological significance of these modifications is linked with the mechanism of action of these drugs. In the short term, glutathione-based systems should continue to provide viable targets and a platform for the development of novel cancer drugs.
Topics: 4-Aminobenzoic Acid; Animals; Antineoplastic Agents; Azo Compounds; Cisplatin; Cytotoxins; Drug Combinations; Glutathione; Glutathione Disulfide; Glutathione Transferase; Humans; Molecular Structure; Neoplasms; Oxidative Stress; Prodrugs; Protein Kinases; Signal Transduction; para-Aminobenzoates
PubMed: 16399394
DOI: 10.1016/S0076-6879(05)01019-0 -
Molecular Cancer Therapeutics Oct 2002Human ovarian carcinoma cells (C70 and C200) made resistant to cisplatin from A2780 cells demonstrated an approximately 20-fold resistance to the drug. These same cell...
Human ovarian carcinoma cells (C70 and C200) made resistant to cisplatin from A2780 cells demonstrated an approximately 20-fold resistance to the drug. These same cell lines showed no collateral resistance (as compared with the wild-type) to a novel glutathione S-transferase pi-activated prodrug [gamma-glutamyl-alpha-amino-beta[2-ethyl-N,N,N',N'-tetrakis (2-chloroethyl) phosphorodiamidate]-sulfonyl-propionyl-(R)-(-) phenylglycine; TLK286]. Previous results have shown a direct correlation between levels of GST pi expression and cytotoxicity for TLK286 (L. A. Rosario et al., Mol. Pharmacol., 58: 167-174, 2000.). However, protein levels of the isozyme were identical in wild-type C70 and C200 cell lines. In analyzing the DNA repair capacity of C70 and C200, an altered expression of the DNA-dependent protein kinase (DNA-PK) complex (catalytic subunit DNA-PKcs, and the heterodimers Ku70 and Ku80) was found. In C70 and C200 cells, DNA-PKcs was overexpressed at both the transcript and protein levels, whereas amounts of Ku70 and Ku80 were higher only at the level of protein expression. TLK286 in either its parent or activated form inhibited the catalytic kinase activity of purified DNA-PK with an IC50 value of approximately 1 microM. Coimmunoprecipitation of Ku70 after TLK286 treatment of purified DNA-PK and C70 cells showed a drug-induced destabilization of the protein-protein interaction between the catalytic subunit and the Ku heterodimer. Overall, these results implicate inhibition of DNA-PK as a component of TLK286 cytotoxicity and provide a rationale for its use in the clinical management of cisplatin-resistant ovarian cancer.
Topics: Antigens, Nuclear; Catalytic Domain; Cell Survival; Chromatography, High Pressure Liquid; Cisplatin; Cytotoxins; DNA Helicases; DNA-Activated Protein Kinase; DNA-Binding Proteins; Dimerization; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Female; Glutathione; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Immunoblotting; Inhibitory Concentration 50; Isoenzymes; Ku Autoantigen; Models, Chemical; Nuclear Proteins; Ovarian Neoplasms; Precipitin Tests; Prodrugs; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Cells, Cultured
PubMed: 12481432
DOI: No ID Found -
BMC Genomics Jul 2003The ADGE technique is a method designed to magnify the ratios of gene expression before detection. It improves the detection sensitivity to small change of gene... (Comparative Study)
Comparative Study
BACKGROUND
The ADGE technique is a method designed to magnify the ratios of gene expression before detection. It improves the detection sensitivity to small change of gene expression and requires small amount of starting material. However, the throughput of ADGE is low. We integrated ADGE with DNA microarray (ADGE microarray) and compared it with regular microarray.
RESULTS
When ADGE was integrated with DNA microarray, a quantitative relationship of a power function between detected and input ratios was found. Because of ratio magnification, ADGE microarray was better able to detect small changes in gene expression in a drug resistant model cell line system. The PCR amplification of templates and efficient labeling reduced the requirement of starting material to as little as 125 ng of total RNA for one slide hybridization and enhanced the signal intensity. Integration of ratio magnification, template amplification and efficient labeling in ADGE microarray reduced artifacts in microarray data and improved detection fidelity. The results of ADGE microarray were less variable and more reproducible than those of regular microarray. A gene expression profile generated with ADGE microarray characterized the drug resistant phenotype, particularly with reference to glutathione, proliferation and kinase pathways.
CONCLUSION
ADGE microarray magnified the ratios of differential gene expression in a power function, improved the detection sensitivity and fidelity and reduced the requirement for starting material while maintaining high throughput. ADGE microarray generated a more informative expression pattern than regular microarray.
Topics: Cell Division; Cytotoxins; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutathione; Glutathione S-Transferase pi; Glutathione Transferase; HL-60 Cells; Humans; Isoenzymes; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity
PubMed: 12859795
DOI: 10.1186/1471-2164-4-28 -
International Journal of Gynecological... 2005The purpose of this study was to determine the safety and efficacy of TLK286 (TELCYTA(TM)), a glutathione analog prodrug, in patients with platinum and paclitaxel... (Clinical Trial)
Clinical Trial
Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer.
The purpose of this study was to determine the safety and efficacy of TLK286 (TELCYTA(TM)), a glutathione analog prodrug, in patients with platinum and paclitaxel refractory or resistant ovarian carcinoma. Thirty-six patients with measurable disease were enrolled. TLK286 was administered at 1000 mg/m2 intravenously every 3 weeks. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and survival. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Thirty-four platinum refractory or resistant patients (94%) were evaluable for objective tumor response. Five patients (15%) had objective tumor responses, including one durable complete response (CR) of greater than 3 years and continuing. The disease stabilization rate was 50%, including one CR (3%), four partial responses (12%), and 12 durable disease stabilizations (35%). Responses were accompanied by improvement in clinical symptoms and Eastern Cooperative Oncology Group Performance Status (ECOG PS) and decline in CA125 levels. Median survival was 423 days with survival of 60% at 1 year and 40% at 18 months. TLK286 was well tolerated in this population. TLK286 is an active agent in chemotherapy-resistant ovarian cancer. Further studies of TLK286 in platinum and paclitaxel refractory or resistant ovarian cancer are in progress.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Carcinoma; Cisplatin; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Glutathione; Humans; Infusions, Intravenous; Middle Aged; Ovarian Neoplasms; Paclitaxel; Survival Analysis
PubMed: 16014111
DOI: 10.1111/j.1525-1438.2005.00114.x