Phase I Study of Prolonged Low Dose Decitabine (5-Aza-Deoxycytidine, NSC #127716) in Patients With Biopsiable Advanced Cancers Refractory to Standard Therapy
Overview
- Phase
- Phase 1
- Intervention
- decitabine
- Conditions
- Hematopoietic/Lymphoid Cancer
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 42
- Locations
- 1
- Primary Endpoint
- Phase II dose will be defined as the lowest dose at or below the maximum tolerated dose (MTD; based on dose limiting toxicity) consistent with a plateau reduction in DNA methylation in target tumor tissue
- Status
- Terminated
- Last Updated
- 13 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of decitabine in treating patients with metastatic or unresectable refractory solid tumors or lymphomas. Drugs used in chemotherapy, such as decitabine, work in different ways to stop cancer cells from dividing so they stop growing or die
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of single agent decitabine and its toxicity using this schedule in this population of patients with solid tumors or lymphomas. II. Definition of the dose at which tumor DNA demethylation is optimum. III. Definition of the dose at which peripheral blood mononuclear cell (PBMN) demethylation is optimal. IV. Definition of decitabine pharmacokinetics and correlation of plasma concentrations with hypomethylation effects. SECONDARY OBJECTIVES: I. Preliminary assessment of decitabine efficacy (objective response). OUTLINE: This is a dose-escalation study. Patients receive decitabine IV over 1 hour on days 1-5 or on days 1-5 and 8-12. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically confirmed malignancy (solid tumor or lymphoma) that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
- •Patients must have had \>= 1 prior chemotherapy regimen; there is no maximum allowable number of prior regimens, provided all other eligibility criteria are met
- •Patients must be \>= 6 weeks beyond treatment with a nitrosourea or mitomycin-C, \>= 4 weeks beyond other chemotherapy or radiotherapy, and must have recovered to =\< grade 1 toxicity for any treatment-limiting toxicity of prior therapy; (Exception: patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy, provided pelvis, ribs, sternum, scapulae, vertebrae or skull were not included in the radiotherapy field)
- •ECOG performance status =\< 2 (Karnofsky \>= 60%); (Exception: Patients with brain metastases must be ECOG performance status 0-1)
- •Leukocytes \>= 3,000/μL
- •Absolute neutrophil count \>= 1,500/μL
- •Platelets \>= 140,000/μL
- •Total bilirubin =\< 1.0 mg/dL
- •AST(SGOT)/ALT(SGPT) =\< 1.5 X institutional upper limit of normal
- •Creatinine (serum) =\< 1.5 mg/dL
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to =\< grade 1 treatment-limiting toxicity levels for adverse events due to agents administered more than 4 weeks earlier; (Exception: patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, ribs, sternum, scapulae, vertebrae or skull were not included in the radiotherapy field)
- •Patients who have had surgery within 2 weeks prior to entering the study
- •Patients may not be receiving any other investigational agents
- •Patients with known brain metastases to whom any of the following apply:
- •Have not received prior cranial irradiation
- •Are requiring \> 8 mg dexamethasone per day (or equivalent other steroid) to maintain an ECOG performance status =\< 1
- •Have had a seizure (focal or generalized) in the last 3 weeks
- •If steroids required to maintain an ECOG performance status =\< 1 have increased in the past 2 weeks
- •Take enzyme-inducing anti-convulsants
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine
Arms & Interventions
Treatment (decitabine)
Patients receive decitabine IV over 1 hour on days 1-5 or on days 1-5 and 8-12. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
Intervention: decitabine
Treatment (decitabine)
Patients receive decitabine IV over 1 hour on days 1-5 or on days 1-5 and 8-12. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
Intervention: pharmacological study
Treatment (decitabine)
Patients receive decitabine IV over 1 hour on days 1-5 or on days 1-5 and 8-12. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Phase II dose will be defined as the lowest dose at or below the maximum tolerated dose (MTD; based on dose limiting toxicity) consistent with a plateau reduction in DNA methylation in target tumor tissue
Time Frame: 4 weeks
Tumor demethylation response, measured by percent change in DNA methylation using the ALU assay
Time Frame: Baseline to day 12 course 1
Analysis of variance with Fisher's protected least significant difference to group dose levels that elicit consistent demethylation response will be used.
Adequacy of peripheral blood mononuclear cell DNA methylation as a surrogate for tumor DNA methylation, measured by effect of dose on reduction in DNA methylation in peripheral blood mononuclear cells
Time Frame: Day 12 course 1
Pharmacokinetic parameters, including Cmax, Tmax, AUC, t ½ α, t ½ β, Vd, and clearance
Time Frame: Days 1 and 5 of course 1
Secondary Outcomes
- Response using RECIST(Up to 4 years)