Inhibition of DNA Methylation by 1-Hr Infusion of 5-aza-2'-Deoxycitidine (Decitabine) x 10 Days (M-F) With Escalating Doses of Sub-Q Pegylated (PEG) Interferon-alpha 2B (PEG-Intron): A Phase I Study With Molecular Correlates
Inhibition of DNA Methylation by 1-Hr Infusion of 5-aza-2'-Deoxycitidine (Decitabine) x 10 Days (M-F) With Escalating Doses of Sub-Q Pegylated (PEG) Interferon-alpha 2B (PEG-Intron): A Phase I Study With Molecular Correlates
This phase I trial is studying the side effects of decitabine when given together with or without interferon alfa-2b, and the best dose of interferon alfa-2b, in treating patients with unresectable or metastatic solid tumors. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Biological therapies, such as interferon alfa-2b, may stimulate the immune system in different ways and stop tumor cells from growing. It is not yet known whether decitabine is more effective when given with or without interferon alfa-2b in treating solid tumors.
PRIMARY OBJECTIVES:
I. To assess toxicities of decitabine plus escalating doses of pegylated interferon alfa-2b (PEG-Intron) in patients with metastatic solid tumor.
II. To identify the dose-limiting toxicity of decitabine in combination with escalating doses of pegylated interferon alfa-2b in these patients.
III. To identify the maximum tolerated dose of pegylated interferon alfa-2b in combination with decitabine in these patients.
SECONDARY OBJECTIVES:
I. To evaluate pretreatment and post-treatment blood and tumor samples to identify changes in global (genomic) DNA methylation.
II. To evaluate pretreatment and post-treatment blood, skin and tumor samples to identify changes in Mage-1 mRNA and protein expression, DNMT-1 levels (due to sequestration by 5-azacytidine), p53 induction (evidence of DNA damage response), as well as changes in levels of 2'5'-oligoadenylate synthesis, MxA and HLA class I as indicators of interferon response.
III. To evaluate complete and partial response rates in patients receiving decitabine in combination with escalating doses of pegylated interferon alfa-2b.
OUTLINE:
This is a dose-escalation study of pegylated interferon alfa-2b. Patients are assigned to 1 of 2 treatment groups.
GROUP 1 (control): Patients receive decitabine IV over 1 hour on days 1-5 and 8-12. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression after the first course of treatment may crossover to receive treatment in group 2.
GROUP 2: Patients receive decitabine as in group 1 and pegylated interferon alfa-2b subcutaneously on days 1, 8, 15, and 22.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample, normal skin, and tissue biopsy collection at baseline and periodically during study. Blood, normal skin, and tissue samples are analyzed for global (genomic) DNA methylation (gene-promoter methylation, gene and protein expression, p53 induction by DNA damage) and interferon levels by high-performance (pressure) liquid chromatography and PCR methylation assays, and for pharmacodynamic studies.
After completion of study treatment, patients are followed at 28 days and then every 3 months.
Inclusion Criteria:
Biopsy-proven solid tumor
Tumor amenable to biopsy
No curative or more effective treatment for this disease exists, in the opinion of the investigator
Measurable disease by scans as assessed by RECIST criteria
No untreated brain metastasis
Zubrod performance status of 0-2
Bilirubin ≤ 1.5 times upper limit normal (ULN)
SGOT or SGPT ≤ 2.5 times ULN (≤ 5 ULN if hepatic metastases present)
Serum creatinine ≤ 1.5 times ULN
Creatinine clearance ≥ 50 mL/min
ANC > 1,500/μL
Platelet count > 100,000/μL
Hemoglobin > 9 g/dL (transfusion allowed)
No NYHA class III-IV cardiac problems (e.g., congestive heart failure or myocardial infarction within the past 2 months)
No severe and/or uncontrolled concurrent medical disease (e.g., uncontrolled diabetes, uncontrolled chronic renal or liver disease, or active uncontrolled infection [e.g., HIV])
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and for 3 months after completion of study therapy
Willing to undergo biopsies
No medical or psychological conditions that, in the opinion of the investigator, may preclude the patient's ability to tolerate or complete the treatment, or to grant reliable informed consent
No other prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I, II, or III cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years
No prior extensive pelvic irradiation or prolonged nucleoside analogue pretreatment
At least 28 days since prior and no concurrent chemotherapy, radiotherapy, surgery, biological therapy, anticancer agent, or other investigational drug