R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To assess the safety and maximum tolerated dose (MTD) of the addition of lenalidomide to
the R-ICE chemoimmunotherapy regimen (lenalidomide-rituximab-ifosfamide-carboplatin-etoposide
[R2ICE]) for the treatment of primary-refractory/first-relapse B-cell lymphoma. (Phase I) II.
To determine if the addition of lenalidomide (based on dose determination from phase I) to
the R-ICE chemoimmunotherapy regimen (R2-ICE) would lead to clinically meaningful improvement
in the overall response rates (ORR) for patients with first-relapse/refractory diffuse large
B-cell lymphoma (DLBCL). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the effect of the addition of lenalidomide to RICE on the number (percentage)
of patients proceeding to stem cell transplant (SCT).

II. To evaluate the effect of the addition of lenalidomide to RICE on other surrogate outcome
measures including complete metabolic response (CMR) rate and overall survival.

III. To describe the toxicities associated with the addition of lenalidomide to the R-ICE
chemoimmunotherapy regimen (R2ICE).

TERTIARY OBJECTIVES:

I. To evaluate ORR based on germinal center B-cell-like (GCB) versus non-GCB subtypes.

II. To evaluate ORR based on percent standardized uptake value (SUV) reduction and percent
anatomic size reduction on interim positron emission tomography (PET)/computed tomography
(CT) scans.

III. To evaluate ORR based on minimal residual disease (MRD) detection (positive versus [vs.]
negative) and quantification after 2 cycles of treatment.

IV. Future tissue and blood based studies.

OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II
study.

Patients receive lenalidomide orally (PO) daily on days 1-14, rituximab intravenously (IV) on
day 1, ifosfamide IV over 24 hours on day 2, carboplatin IV over 1-2 hours on day 2, and
etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the
absence of disease progression or unacceptable toxicity. Patients achieving CMR, partial
metabolic response (PMR), or no metabolic response (NMR) may receive 2 more courses per
physician discretion. After completion of 2 cycles of R2ICE treatment, patients achieving
objective status of CMR, PMR or NMR may proceed to SCT during the event monitoring phase.

After completion of study treatment, patients are followed up every 3 months for 3 years and
then every 6 months for 2 years.

Inclusion Criteria:

- Histological confirmation of expressing CD20 antigen as determined by pathology at the
respective institution and central pathology review at Mayo Clinic Rochester; Notes:
for phase I, all types of B-cell lymphomas are allowed to participate; for phase II,
only DLBCL patients are allowed to participate; for phase I only, patients with
primary mediastinal large B-cell (PMLBCL) or transformed lymphoma are allowed to
participate; additional notes regarding slide submission: central pathology review is
mandatory, but is retrospective in nature; slides must be submitted =< 30 days after
registration to allow for confirmation of DLBCL diagnosis and to have sufficient
material for GCB/ABC assessment by a gene-expression profiling method; patients can be
enrolled prior to submission of slides; for phase II, if central review of pathology
shows that the patient does not have DLBCL or the amount of formalin-fixed
paraffin-embedded (FFPE) material is not considered sufficient for cell-of-origin
(COO) analysis, the patient may remain on the study but the patient should be replaced

- Measurable disease (at least 1 lesion >= 1.5 cm in diameter) as detected by PET/CT

- Only 1 line of previous anti-lymphoma therapy is allowed and not currently receiving
any other agent that would be considered as a treatment for the lymphoma; patients
must be >= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or
rituximab up to 1 week prior to registration for management of symptoms is allowed

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- Absolute neutrophil count (ANC) >= 1500/mm^3, obtained =< 7 days prior to registration

- Platelet count >= 75,000/mm^3, obtained =< 7 days prior to registration

- Total bilirubin =< 2 x upper limit of normal (ULN) (unless related to lymphoma or
Gilbert?s disease) OR =< 5 x ULN for subjects with documented or suspected Gilbert?s
disease, or related to involvement of the liver by the lymphoma, obtained =< 7 days
prior to registration

- Aspartate transaminase (AST) and alanine aminotransferase (ALT) (serum glutamate
pyruvate transaminase [SGPT]) =< 3 x ULN unless evidence of the direct liver and/or
bone involvement by lymphoma, then =< 5 x ULN, obtained =< 7 days prior to
registration

- PHASE I: Subjects must have calculated creatinine clearance >= 60 ml/min by
Cockcroft-Gault formula, obtained =< 7 days prior to registration

- PHASE II: Subjects must have calculated creatinine clearance >= 30 ml/min by
Cockcroft-Gault formula, obtained =< 7 days prior to registration

- For women of childbearing potential only: Negative pregnancy test =< 10-14 days prior
to registration; NOTE: the patient must have an additional negative pregnancy test =<
24 hours prior to receiving the initial prescription of lenalidomide, per requirements
of the REVLIMID Risk Evaluation and Mitigation Strategies (REMS) program

- Provide informed written consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study [i.e. active treatment and observation])

- Willing to provide blood samples for correlative research purposes

- Considered transplant-eligible, as determined by the opinion of the investigator at
the participating institution; the participating institution does not need to be a
transplant center but patients can be referred to a transplant center if needed

- Willing and able to register into and comply with the mandatory requirements of
Celgene?s REVLIMID REMS program

- Females of reproductive potential are willing and able to adhere to the scheduled
pregnancy testing as required by Celgene?s REVLIMID REMS program

- Willing and able to take aspirin (81 mg) daily as prophylactic anticoagulation
(patients intolerant to acetylsalicylic acid [ASA] may use warfarin or low molecular
weight heparin)

Exclusion Criteria:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- NOTE: patients unwilling or unable to do any of the following are also excluded:

- Men must agree to use a latex condom during sexual contact with a female of
child-bearing potential even if they have had a successful vasectomy

- Women of child bearing potential must agree to use 2 methods of reliable
contraception simultaneously

- All patients must be counseled at a minimum of every 28 days about pregnancy
precautions and risks of fetal exposure

- Co-morbid systemic illnesses or other severe concurrent disease which, 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 including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy; NOTE: patients known to be
HIV positive, but without clinical evidence of an immunocompromised state, are
eligible for this trial; patients with HIV on antiretroviral therapy other than
zidovudine (AZT) and/or stavudine and without prior acquired immunodeficiency syndrome
(AIDS) defining conditions and adequate CD4 count (> 400) are eligible

- History of myocardial infarction =< 180 days prior to registration or congestive heart
failure requiring use of ongoing maintenance therapy for life-threatening ventricular
arrhythmias

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm; patients must be >= 2 weeks from prior anti-lymphoma therapy;
the use of steroids and/or rituximab up to 1 week prior to registration for management
of symptoms is allowed

- Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanotic
skin cancer, carcinoma-in-situ of the cervix, or any cancer that, in the judgment of
the investigator, has been treated with curative intent and will not interfere with
the study treatment plan and response assessment; NOTE: if there is a history of prior
malignancy, they must not be receiving other specific treatment such as radiation,
chemotherapy, or immunotherapy for their cancer

- Unable or unwilling to take any prophylaxis; patients with history of or new/active
deep vein thrombosis/embolism/thrombophilia are allowed to participate if they are on
appropriate therapeutic anticoagulation during the treatment on the trial; these
patients would not need the aspirin with the lenalidomide unless clinically indicated;
therefore, patients must be able and willing to receive anticoagulation (prophylaxis
versus therapeutic as clinically indicated)

- History of radiation therapy to >= 25% of the bone marrow for other diseases

- Receiving erythroid stimulating agents (epoetin alfa [EPO]: Procrit, Aranesp)

- Patients with active or prior central nervous system (CNS) lymphoma or cerebrospinal
fluid involvement with malignant lymphoma cells; NOTE: these patients are usually
treated with CNS directed therapy; screening for cerebrospinal fluid (CSF)/CNS
involvement is NOT required but can be performed per treating medical doctor (MD)
discretion

- Active hepatitis B as defined by seropositivity for hepatitis B surface antigen
(HBsAg); subjects with positive hepatitis B core antibody titers and normal liver
transaminases are allowed provided that antiviral prophylaxis is administered per
institutional guidelines; NOTE: subjects with hepatitis C antibody will be eligible
provided that they do not have elevated liver transaminases or other evidence of
active hepatitis