Cyclophosphamide and Alemtuzumab In Lymphoma

This research study is a Phase I clinical trial, which tests the safety of an investigational
intervention and also tries to define the appropriate dose of the investigational
intervention to use for further studies. "Investigational" means that the intervention is
being studied.

The FDA (the U.S. Food and Drug Administration) has not approved alemtuzumab for aggressive
lymphoma but it has been approved for other uses.

In this research study, the investigators are studying the combination of cyclophosphamide
and alemtuzumab in participants with several types of aggressive lymphoma which are positive
for a protein called CD52, the target of alemtuzumab. Studies in laboratory models of CD52
positive lymphoma showed the combination of cyclophosphamide and alemtuzumab was very
effective. Cyclophosphamide causes a specific type of immune cell, called a macrophage, to
attack lymphoma cells treated with alemtuzumab. Both drugs have been used in participants
with lymphoma but have not been previously combined in this way. The investigators hope to
identify the highest dose of the drugs that can be safely given together and to see if the
combination if effective in treating these lymphomas.

Inclusion Criteria:

- Participants must have histologically confirmed non-Hodgkin lymphoma and be considered
ineligible for standard curative therapeutic options, including high dose chemotherapy
with autologous stem cell rescue.

- Participants with the following subtypes of CD52 positive non-Hodgkin lymphoma
(defined as ≥ 50% positive staining by immunohistochemical staining or flow cytometry
by local lab) will be considered eligible:

- High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (DHL)

- DLBCL or high-grade B-cell lymphoma NOS or B-cell lymphoma unclassifiable with
features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma with
MYC and BCL2 protein over-expression by immunohistochemical (IHC) staining as defined
by MYC expression in ≥ 40% of cells and BCL2 positivity ≥ 50% (DOL)

- Transformed lymphoma with MYC rearrangement by FISH or over-expression by IHC, as
above

- CD52 positive mature T-cell lymphoproliferative disorder

- There is no limit to the prior number of chemotherapy regimens. Patients with prior
autologous or allogeneic stem cell transplantation, as well as prior therapy with
cyclophosphamide or alemtuzumab, are eligible.

- Age ≥ 18 and ≤75

- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

- Participants must have normal organ and marrow function as defined by peripheral blood
values below:

- leukocytes ≥1,000/mcL

- absolute neutrophil count ≥500/mcL

- platelets ≥25,000/mcL

- total bilirubin ≤ 2 × institutional upper limit of normal (ULN) unless related to
Gilbert's disease

- AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

- creatinine clearance < 1.5 x institutional ULN

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants who have had chemotherapy or radiotherapy within 1 weeks (4 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Participants who are receiving any other investigational agents for their lymphoma.

- Participants receiving corticosteroids within the past 1 week.

- Participants with known active CNS involvement by lymphoma should be excluded from
this clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.

- History of allergic reactions attributed to cyclophosphamide or alemtuzumab

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled hematuria related to bladder injury or psychiatric
illness/social situations that could limit compliance with study requirements.

- Pregnant women are excluded from this study because cyclophosphamide and alemtuzumab
at these doses have the potential for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for adverse events in nursing infants secondary
to treatment of the mother with these agents, breastfeeding should be discontinued.
Negative serum pregnancy test will be required for women of childbearing potential.

- HIV-positive participants on combination antiretroviral therapy are ineligible because
of the increased risk of lethal infections when treated with marrow-suppressive
therapy.