Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors : Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients With Advanced Solid Tumors
Background:Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes. Two DNA hypomethylating nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have been approved by the FDA for the treatment of patients with myelodysplastic syndromes and certain leukemias.The nucleoside analog 4'-thio-2'-deoxycytidine (TdCyd) is incorporated into DNA where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in reactivation of tumor suppressor genes.Data generated at Southern Research Institute and the NCI suggest a correlation between TdCyd activity in solid tumor xenograft models and decreased levels of DNMT1.TdCyd offers an improvement over current DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; treatment with TdCyd is anticipated to result in the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.Two patients on dose levels 6 and 7 developed Pneumocystis jiroveci pneumonia (PJP) so all patients will be administered PJP prophylaxis.Primary Objective:-To establish the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles, to patients with refractory solid tumorsSecondary Objectives:To determine the pharmacokinetics of oral TdCydTo document preliminary evidence of TdCyd activityTo determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cellsEligibility:-Patients must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapyStudy Design:TdCyd will be administered orally once a day for 5 days of each week for 2 weeks, with one week off, in 21-day cycles.The trial will follow an accelerated titration design, changing to a traditional 3+3 dose escalation design (3-6 patients per cohort) once specified toxicity criteria are met. Intrapatient dose escalation will be allowed.Blood samples will be obtained for pharmacokinetic analysis and to isolate circulating tumor cells to assess re-expression of genes silenced by methylation..
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Klinische Studie| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ClinicalTrials.gov - (2024) vom: 26. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
610 |
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| Anmerkungen: |
Source: Link to the current ClinicalTrials.gov record., First posted: April 22, 2015, Last downloaded: ClinicalTrials.gov processed this data on April 03, 2024, Last updated: April 03, 2024 |
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| PPN (Katalog-ID): |
CTG000047112 |
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| 500 | |a Source: Link to the current ClinicalTrials.gov record., First posted: April 22, 2015, Last downloaded: ClinicalTrials.gov processed this data on April 03, 2024, Last updated: April 03, 2024 | ||
| 520 | |a Background:Methylation-mediated silencing of genes is an epigenetic mechanism implicated in carcinogenesis; agents that inhibit this mechanism are of clinical interest because of their potential to re-activate silenced tumor suppressor genes. Two DNA hypomethylating nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have been approved by the FDA for the treatment of patients with myelodysplastic syndromes and certain leukemias.The nucleoside analog 4'-thio-2'-deoxycytidine (TdCyd) is incorporated into DNA where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in reactivation of tumor suppressor genes.Data generated at Southern Research Institute and the NCI suggest a correlation between TdCyd activity in solid tumor xenograft models and decreased levels of DNMT1.TdCyd offers an improvement over current DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; treatment with TdCyd is anticipated to result in the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well tolerated in extended dosing schedules.Two patients on dose levels 6 and 7 developed Pneumocystis jiroveci pneumonia (PJP) so all patients will be administered PJP prophylaxis.Primary Objective:-To establish the safety, tolerability, and MTD of oral TdCyd administered daily for 5 days a week for 2 weeks, with one week off, q 21-day cycles, to patients with refractory solid tumorsSecondary Objectives:To determine the pharmacokinetics of oral TdCydTo document preliminary evidence of TdCyd activityTo determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cellsEligibility:-Patients must have histologically documented solid tumors whose disease has progressed on standard therapy or for which there is no available standard therapyStudy Design:TdCyd will be administered orally once a day for 5 days of each week for 2 weeks, with one week off, in 21-day cycles.The trial will follow an accelerated titration design, changing to a traditional 3+3 dose escalation design (3-6 patients per cohort) once specified toxicity criteria are met. Intrapatient dose escalation will be allowed.Blood samples will be obtained for pharmacokinetic analysis and to isolate circulating tumor cells to assess re-expression of genes silenced by methylation. | ||
| 650 | 2 | |a Neoplasms | |
| 650 | 4 | |a Study Type: Interventional | |
| 650 | 4 | |a Recruitment Status: Suspended | |
| 650 | 4 | |a Phase: Phase 1 | |
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