Veltuzumab and Milatuzumab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

A phase I/II study of veltuzumab combined with milatuzumab in relapsed and refractory
non-Hodgkin's lymphoma. Both agents are well-tolerated in early phase clinical testing with
infusion reactions as the primary observed toxicity. Preclinical testing in vitro and in
vivo have demonstrated single agent activity for both veltuzumab and milatuzumab. In mantle
cell lymphoma cell lines and SCID mouse models, synergist effects were observed when
milatuzumab was combined with rituximab. Veltuzumab has several advantages over rituximab
including slower off-rates, shorter infusion times, higher potency, and improved therapeutic
responses in animal models. Previous and ongoing clinical investigations support the concept
of combining monoclonal antibodies in NHL.

Inclusion Criteria:

- Histologically confirmed B-cell non-Hodgkin lymphoma (NHL), including any of the
following:

- Marginal zone lymphoma

- Waldenstrom macroglobulinemia (lymphoplasmacytic lymphoma)

- Follicular lymphoma

- Mantle cell lymphoma

- Relapsed or refractory disease after ≥ 1 prior therapy

- Patients with rituximab-refractory disease (defined as having less than a partial
response to the prior rituximab-containing regimen) or rituximab-sensitive disease
(defined as having a complete response or partial response to the last
rituximab-containing regimen [provided it has been ≥ 3 months since the last dose of
rituximab]) are eligible.

- Age >18 years.

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

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1000/μL

- Platelets ≥ 75,000/μL

- Total bilirubin ≤ 2.0 X institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal

- Creatinine ≤ 2.0 mg/dL

- Patients who have relapsed after stem cell transplant are eligible for this trial.

- Patients with active Hepatitis B infection are not eligible.

- Non-pregnant and non-nursing. Women of child bearing potential and men must agree to
use contraception prior to study entry and for duration of study participation.

- Must possess the ability to understand and the willingness to sign a written informed
consent document.

Phase II

-Must have measurable disease, defined as at least one lesion that can be accurately
measured in at least one dimension >10 mm or in the case of Waldenstrom's
macroglobulinemia, the presence of an IgM paraprotein level 2x the upper limit of normal.

Exclusion Criteria:

- Must be recovered from all toxicities from prior therapy or radiation (excluding
alopecia).

- No known CNS lymphoma.

- History of documented human anti-globulin antibodies.

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations.

- HIV-positive patients.

- Pregnant women.

- Patients with secondary malignancies with exception of non-melanomatous skin cancers.