Low Dose Decitabine + Interferon Alfa-2b in Advanced Renal Cell Carcinoma

Phase II Study of Low Dose Decitabine (5-Aza-Deoxycytidine) With Interferon Alfa-2b in Advanced Renal Cell Carcinoma

Primary Objective:

• To determine the progression-free survival (PFS) times for patients with advanced renal cell carcinoma (RCC) treated with decitabine and interferon alfa-2b.

Secondary Objectives:

• To determine the toxicity of the combination of decitabine and interferon alfa-2b at the proposed dose and schedule in patients with advanced RCC
• To determine overall response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for patients with advanced RCC treated with decitabine and interferon alfa-2b.
• To determine the overall survival times for patients with advanced RCC treated with decitabine and interferon.
• To study the effects of decitabine and interferon alfa-2b on DNA methylation and gene expression in patients' tumor and non-tumor tissues and their correlation with clinical outcomes.
• To characterize the modulation of cellular immunity induced by the combination of decitabine and interferon alfa-2b in patients with advanced RCC and to correlate these results with clinical outcomes.

THE STUDY DRUGS:

Decitabine is designed to slow tumor growth and may cause death of cancer cells.

Interferon alfa-2B is designed to activate your immune system, which may help keep tumors from growing, and may shrink tumors.

STUDY TREATMENT:

If you are found to be eligible to take part in this study, you will receive decitabine by vein over 1 hour on Days 1-5 of each cycle. A cycle in this study is 28 days long. All treatments with decitabine will take place at M. D. Anderson.

Once you have completed 2 cycles of decitabine (on Day 1 of Cycle 3), you will begin taking interferon alfa-2b twice each day (morning and afternoon) while continuing the same 5-day dosing schedule for decitabine. Interferon alfa-2b will be given as a subcutaneous (just under the skin) injection. It can be given by yourself or a caregiver at home or by your local doctor. You and your caregiver will be taught how to do the injection.

STUDY VISITS:

You will have the following tests/procedures performed during clinic visits.

On Day 1 of each cycle:

• You will have a physical exam, including measurement of your vital signs and weight.
• You will be asked about any medications or treatments you may be currently receiving.
• You will have a performance status evaluation.
• You will be asked about any side effects you may have experienced since your last visit. You will have blood drawn (about 1 teaspoon) for routine testing.

Beginning in Cycle 3, you will be required to return to the clinic around Day 14 of each cycle to have the following tests:

• You will have blood drawn (about 1 teaspoon each time) once a week for routine tests. If you do not experience severe side effects during Cycles 3 and 4, you will no longer be required to have weekly routine blood testing. Instead, you will return to have routine blood drawn on Day 1 of each cycle. This once-weekly schedule will restart if you experience severe side effects in Cycle 5.
• You will have a CT or MRI scan to check the status of the disease.
• Your vital signs will be measured
• You will be asked about any side effects you may have experienced since your last visit.

LENGTH OF STUDY:

You will continue taking the study drug combination unless the disease gets worse, you develop an illness that does not allow you to continue receiving the study therapy, or you experience any intolerable side effects. If any of these things occur, you will be removed from this study.

This is an investigational study. Decitabine is FDA approved and commercially available for the treatment of myelodysplastic syndrome (MDS). Interferon alfa-2b is FDA approved and commercially available for the treatment of several types of cancer, such as malignant melanoma, hairy cell leukemia, and non-Hodgkin's lymphoma. Their use together in this study in the treatment of PRC is investigational and authorized for use in research only.

Up to 60 patients will take part in this study. All will be enrolled at M. D. Anderson.

Inclusion Criteria:

• Patients must have histologically confirmed clear cell renal carcinoma that is metastatic or unresectable. In the absence of metastatic disease, patients who are deemed unresectable or inoperable will have a documented surgical opinion confirming this. Surgical opinion will be rendered either by surgical consultation or after presentation at our interdisciplinary conference. Patients with locally recurrent RCC are eligible, if surgical resection of local recurrence is not feasible or is refused by patient.

• Patients with locally advanced unresectable RCC should have measurable or evaluable metastatic disease to be eligible for the protocol. Patients with bilateral renal cancer are eligible as long as both cancers are of clear cell type and patients have metastatic or unresectable disease.

• Patients may have received up to two prior anti-cancer therapies (including receptor tyrosine kinase inhibitors or cytokine therapy) but no prior chemotherapy for renal cell carcinoma. Patients should have received prior standard therapy, or otherwise deemed ineligible for such therapies.

• Patients must have measurable or clinically evaluable disease as defined by RECIST criteria.

• Patients must be >/= 14 days beyond the last administration of anti-cancer therapy, and must have recovered from the toxicities of prior therapy.

• Patients must be >/= 18 years of age.

• ECOG performance status </= 2 (Karnofsky >/= 60%).

• Patients must have adequate organ and marrow function, measured within 14 days of study entry, as defined below:

  • All Patients: Absolute neutrophil count >/= 1,500/microL; Platelets >/= 100,000/microL; Creatinine (serum) </= 2.0 mg/dL
  • Patients without liver metastases: Total bilirubin </= 1.5 mg/dL; AST(SGOT)/ALT(SGPT) </= 2.5 X Institutional Upper Limit of Normal (IULN)
  • Patients with liver metastases: Total bilirubin </= 1.5 x IULN; AST(SGOT)/ALT(SGPT) </= 5 x IULN

• The effects of decitabine and interferon on the developing human fetus are unknown. For this reason and because chemotherapy agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• Female patients of childbearing potential should have a normal plasma beta human chorionic gonadotropin (betaHCG).

• Patients must give written informed consent prior to initiation of therapy in keeping with the policies of the institution. Patients with a history of major psychiatric illness must be judged able to fully understand the investigational nature of this study and the risks associated with the therapy.

Exclusion Criteria:

• Patients with active autoimmune disorders or who are receiving immunosuppressive therapy (including steroids or methotrexate) for any indication.
• Patients may not receive any other investigational agents within two weeks of study entry. Patients may not receive any other investigational agents while on study.
• Patients who have had major surgery within 2 weeks prior to entering the study, or have otherwise not adequately recovered from prior surgery.
• Patients who have had palliative radiation therapy within 1 week prior to entering the study.
• Patients with untreated or symptomatic brain metastases.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or potentially life-threatening cardiac arrhythmia.
• Psychiatric illness or social situations which in the opinion of the investigator could interfere with the completion of the proposed treatment.
• Pregnant women are excluded from this study because decitabine is an antimetabolite with the potential for teratogenic or abortifacient effects and interferon alfa-2b has abortifacient activity in animal studies. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with decitabine, breastfeeding should be discontinued if the mother is treated with decitabine or decitabine and interferon.
• Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, patients known to be HIV-positive and receiving anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study agents.