A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
|Solid Tumors Virally Mediated Cancers and Liposarcoma||Drug: oral 5-azacitidine in combination with romidepsin||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase I Trial of Oral 5-azacitidine With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma|
- Incidence of adverse events [ Time Frame: From first dose of study treatment to end of study visit, approximately 1.5 years ]Incidence of adverse events, serious adverse events, and dose-limiting adverse events graded according to NCI CTCAE version 4
- Maximum Tolerated Dose (MTD) [ Time Frame: First cycle ]MTD defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
- Clinical responses associated with oral 5-azacitidine and romidepsin [ Time Frame: Measured every two cycles during study treatment, expected duration ≤1.5 years ]Clinical responses associated with oral 5-azacitidine and romidepsin treatment in subjects with advanced solid malignancies according to RECIST criteria [Time Frame: measured every two cycles during study treatment, expected duration ≤1.5 years
- Peak plasma concentration (Cmax) [ Time Frame: On Day 1 and 8 of Cycle 1 ]Peak plasma concentration (Cmax), area under the concentration versus time curve (AUC) from time 0-infinity, elimination half-life (t1/2), clearance, and volume of distribution (Vd)
- Determine whether changes in DNA methylation, histone acetylation, and/or gene expression correlates with clinical response to oral 5-azacitidine and romidepsin [ Time Frame: Weekly during cycle 1 and at the start of each subsequent cycle while on study ]
|Study Start Date:||February 2012|
|Study Completion Date:||September 2016|
|Primary Completion Date:||March 2016 (Final data collection date for primary outcome measure)|
Experimental: oral 5-azacitidine + romidepsin
oral 5-azacitidine in combination with romidepsin
Drug: oral 5-azacitidine in combination with romidepsin
Table 1: Dose Escalation Schedule Dose Level Dose and Schedule a, c 5-Azacitidine (PO) Romidepsin (IV)
Level -1b 100mg daily days 1-14 8mg/m2 days 8 and 15
Level 1 200mg daily days 1-14 8mg/m2 days 8 and 15
Level 2 300mg daily days 1-14 8mg/m2 days 8 and 15
Level 3 300mg daily days 1-21 8mg/m2 days 8 and 15
Level 4d MTD 8mg/m2 days 8, 15, and 22
This is a two part, single-institution, open-label, Phase I dose-escalation study of oral 5-azacitidine in combination with intravenous (IV) romidepsin. Part 1 of the study is a traditional 3 + 3 dose escalation study designed to evaluate the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) profiles, and pharmacodynamic profiles of increasing doses of orally administered 5-azacitidine in combination with a constant dose of IV romidepsin. Part 2 is an expansion cohort study for the preliminary evaluation of efficacy in the treatment of virally mediated cancers and liposarcoma once the MTD has been determined. PK and PD data will also be collected for these subjects.
- Plasma samples will be obtained, prior and during treatment, to assess the methylation status of free tumor DNA circulating in the blood
- Archival tissue will be obtained on all participants for future correlative studies, such as baseline gene expression, methylation patterns.
- Participants with accessible, biopsiable tumors will also undergo pre-treatment and post-treatment (~cycle 2D1) biopsies for correlative studies in the expansion cohort.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01537744
|United States, Maryland|
|Sidney Kimmel Cancer Center @ Johns Hopkins|
|Baltimore, Maryland, United States, 21231|
|Principal Investigator:||Nilofer Azad, MD||Sidney Kimmel Comprehensive Cancer Center|