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

Study Overview
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Brief Summary
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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.

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

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: cyclophosphamide
* Drug: vincristine
* Drug: doxorubicin
* Drug: prednisone
* Drug: azacytidine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All patients<br>subjects will receive azacytidine dose dependent on dose-escalation schedule at time of enrollment - all will receive standard dose RCHOP | Biological: rituximab<br>* 375 mg/m2 on Day 8 of each of 6 cycles<br>Drug: cyclophosphamide<br>* 750 mg/m2 on Day 8 of each of 6 cycles<br>Drug: vincristine<br>* 1.4 mg/m2 on Day 8 of each of 6 cycles<br>Drug: doxorubicin<br>* 50 mg/m2 on Day 8 of each of 6 cycles<br>Drug: prednisone<br>* 100 mg PO days 8-12 of each of 6 cycles<br>Drug: azacytidine<br>* Dose level 1: azacytidine 25 mg/m2 days 1-5 Dose level 2: azacytidine 50 mg/m2 days 1-5 Dose level 3: azacytidine 75 mg/m2 days 1-5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response | Complete Response | 13 months |