Phase I/II Trial of R-CHOP + Azacytidine in Diffuse Large B Cell Lymphoma

This is a phase I/II open label, multi-center study of azacytidine in combination with standard RCHOP therapy in patients with DLBCL. Patients will be treated with azacytidine at escalating doses on days 1-5, followed by standard dose rituximab plus CHOP chemotherapy on day 8, every 21 days. Patients will be treated for a total 6 cycles. The phase II portion will then evaluate efficacy of the combination at the established MTD.


Eligibility Criteria:
Inclusion Criteria:

* Patients must have histologically confirmed DLBCL with characteristic immunophenotypic profiles. Tumor tissue must be confirmed to express the CD20 antigen by flow cytometry or immunohistochemistry.
* Patients must have at least one site of measurable disease, 1.5 cm in diameter or greater.
* Patient has not had any previous treatment.
* Stage II (not appropriate for abbreviated chemoimmunotherapy and radiotherapy), III or IV disease
* Able to adhere to the study visit schedule and other protocol requirements.
* Patients must have laboratory test results within these ranges:

  * Absolute neutrophil count \> = 1500/mm³
  * Platelet count \> = 75,000/mm³
  * Serum creatinine \< = 1.5X upper limit of normal (ULN)
  * Total bilirubin \< = 1.5X ULN. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis.
  * AST (SGOT) and ALT (SGPT) \< = 2 x ULN
* Disease free of prior malignancies for \> = 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
* Women of childbearing potential must have a negative serum pregnancy test prior to azacitidine treatment.
* Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment with azacitidine. The effects of azacytidine on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, 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.
* Age \>18 years.
* Ability to understand and the willingness to sign a written informed consent document.
* ECOG performance status of 0-2

Exclusion Criteria:

* Patients must not have any serious medical condition, laboratory abnormality,or psychiatric illness that would prevent the subject from signing the informed consent form.
* Patients must not have any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
* Use of any other experimental drug or therapy within 28 days of baseline.
* Concurrent use of other anti-cancer agents or treatments.
* Known positive for HIV or infectious hepatitis B.
* Known central nervous system involvement by lymphoma.
* Known or suspected hypersensitivity to azacitidine or mannitol.
* Patients must not have advanced malignant hepatic tumors.
* Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown.