Everolimus, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Untreated Diffuse Large B-Cell Lymphoma
Everolimus, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Untreated Diffuse Large B-Cell Lymphoma
RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the enzymes
 needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer cells in
 different ways. Some block the ability of cancer cells to grow and spread. Others find cancer
 cells and help kill them or carry cancer-killing substances to them. Drugs used in
 chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and
 prednisone, work in different ways to stop the growth of cancer cells, either by killing the
 cells or stopping them from dividing. Giving everolimus together with rituximab,
 cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone may kill
 more cancer cells.

 PURPOSE: This phase I trial is studying the side effects and the best dose of everolimus when
 given together with rituximab and combination chemotherapy in treating patients with newly
 diagnosed untreated diffuse large B-cell lymphoma.
OBJECTIVES:

 Primary

 -  To establish the maximum-tolerated dose (MTD) of everolimus in combination with R-CHOP
 (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and
 prednisone) chemotherapy.

 -  To assess the feasibility of everolimus in combination with standard R-CHOP chemotherapy
 in patients with newly diagnosed diffuse large B-cell lymphoma.

 Secondary

 -  To describe the toxicities associated with everolimus in combination with R-CHOP
 chemotherapy.

 -  To further describe the toxicities associated with everolimus in combination with R-CHOP
 chemotherapy.

 -  To assess the rate of event-free survival (EFS) at 12 months for diffuse large B-cell
 lymphoma patients treated with everolimus in combination with R-CHOP chemotherapy.

 -  To evaluate overall response rate, complete response rate, duration of response, EFS,
 overall survival, and progression-free survival for patients treated with everolimus in
 combination with R-CHOP chemotherapy.

 Tertiary

 -  To profile gene expression using immunohistochemistry and categorize patients as
 germinal-center B-cell-like (GBC) vs activated B-cell-like (ABC) vs unclassified
 lymphoma subtype. (exploratory)

 -  To determine whether previously identified predictive markers in large cell lymphoma
 remain valid with the addition of everolimus to R-CHOP chemotherapy. (exploratory)

 OUTLINE: This is a multicenter, dose-escalation study of everolimus followed by a feasability
 expanded-cohort study.

 Patients receive everolimus orally (PO) once daily (QD) on days 1-10 or 1-14; rituximab IV,
 cyclophosphamide IV, doxorubicin hydrochloride IV over 15-60 minutes, and vincristine sulfate
 IV on day 1; and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6
 courses in the absence of disease progression or unacceptable toxicity.

 Tumor biopsies are collected for laboratory studies and patients may undergo blood and needle
 biopsy sample collection for correlative studies.

 After completion of study treatment, patients are followed up every 3-6 months for up to 5
 years.
DISEASE CHARACTERISTICS:

 -  Untreated, histological diagnosis of CD20-positive diffuse large B-cell lymphoma

 -  Stage II-IV (Ann Arbor Staging)

 -  Measurable or assessable disease defined as at least one of the following:

 -  A lymph node or tumor mass that is ≥ 2.0 cm in at least one dimension by CT
 portion of PET/CT scan, CT scan, or MRI

 -  Diffuse infiltration of an organ such as the stomach, bone marrow, peripheral
 blood, liver, lungs, or bowel by lymphoma without a discrete mass would
 constitute assessable, but not measurable, disease

 -  Diagnostic tissue slides and paraffin-embedded block must be available

 -  No CNS lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells

 PATIENT CHARACTERISTICS:

 -  ECOG performance status 0-2

 -  Absolute neutrophil count (ANC) ≥ 1,500/mm³

 -  Peripheral platelet count ≥ 100,000/mm³

 -  Hemoglobin (HgB) > 9.0 g/dL

 -  Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

 -  For total bilirubin > 1.5 times ULN, the direct bilirubin must be normal

 -  Alkaline phosphatase ≤ 3 times ULN (≤ 5 times ULN if evidence of direct liver
 involvement by lymphoma)

 -  AST ≤ 3 times ULN (≤ 5 times ULN if evidence of direct liver involvement by lymphoma)

 -  Creatinine ≤ ULN

 -  Negative serum or urine pregnancy test

 -  Not pregnant or nursing

 -  Men or women of childbearing potential must be willing to employ adequate
 contraception throughout the study and for12 months after the last dose of study drug

 -  Willing to return to the National Central Cancer Treatment Group (NCCTG) enrolling
 institution for follow-up

 -  Willing to provide archival tissue from the primary diagnosis (original lymphoma lymph
 node tissue biopsy)

 -  Willing to abstain from eating grapefruit or drinking grapefruit juice for the
 duration of the study

 -  Diabetic patients who are taking insulin or oral anti-diabetic therapy must have HbA1c
 ≤ 8%, or a fasting serum glucose ≤ 110% ULN

 -  HIV-positive patients must have CD4 count ≥ 400/mm³

 -  No co-morbid systemic illnesses or other severe concurrent disease that, in the
 judgment of the investigator, would make the patient inappropriate for entry into this
 study or interfere significantly with the proper assessment of safety and toxicity of
 the prescribed regimens

 -  No immunocompromised patients (other than that related to the use of corticosteroids)
 including patients known to be HIV positive with a CD4 count of < 400/mm³

 -  No uncontrolled intercurrent illness including, but not limited to, any of the
 following:

 -  Ongoing or active infection

 -  Symptomatic congestive heart failure

 -  Unstable angina pectoris

 -  Cardiac arrhythmia

 -  Severely impaired lung function

 -  Uncontrolled diabetes as defined by fasting serum glucose > 1.5 times ULN

 -  Optimal glycemic control should be achieved before starting trial therapy

 -  Psychiatric illness/social situations that would limit compliance with study
 requirements

 -  Liver disease such as cirrhosis or severe hepatic impairment

 -  Chronic active hepatitis

 -  Chronic persistent hepatitis or history of hepatitis B or C

 -  No other active malignancy except non-melanotic skin cancer or carcinoma in situ of
 the cervix

 -  If there is a history of prior malignancy, patients must not be receiving other
 specific treatment (other than hormonal therapy) for their cancer

 -  No positive hepatitis B antigen (HBsAg) or hepatitis C serology (HCV) tests meeting
 the following criteria:

 -  Hepatitis B surface antigen (HbsAg) and antibody to hepatitis B core (anti-HBc)
 or hepatitis C antibody

 -  All patients must be screened prior to registration

 -  Patients who have evidence of chronic or acute infection with either hepatitis B
 or C may not be treated on this protocol

 PRIOR CONCURRENT THERAPY:

 -  Not receiving any other investigational agent that would be considered as a treatment
 for the primary neoplasm

 -  No planned immunization with attenuated live vaccines ≤ 7 days prior to registration
 or during study period

 -  Close contact with those who have received attenuated live vaccines should be
 avoided during treatment with everolimus

 -  Examples of live vaccines include intranasal influenza, measles, mumps, rubella,
 oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines

 -  Not currently on enzyme-inducing anti-convulsants or other strong inducers of CYP3A4
 (efavirenz, nevirapine, barbiturates, carbamazepine, modafinil, phenobarbital,
 phenytoin, rifabutin, rifampin, pioglitazone, or St. John wort) or strong inhibitors
 of CYP3A4 (indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole,
 voriconazole, ketoconazole, nefazodone, saquinavir, or telithromycin)