Safety Study of Different Doses of hA20 (Veltuzumab) in CD20+ Non-Hodgkin's Lymphoma

• Safety of hA20 with this administration schedule and dosing [ Time Frame: first 12 weeks, then over 2 years ] [ Designated as safety issue: Yes ]
• tolerance of hA20 with this administration schedule and dosing [ Time Frame: first 12 weeks ] [ Designated as safety issue: Yes ]
• immunogenicity of hA20 with this administration schedule and dosing [ Time Frame: first 12 weeks, as needed over 2 years ] [ Designated as safety issue: Yes ]

• Pharmacodynamics of hA20 [ Time Frame: first 12 weeks, then up to 2 years ] [ Designated as safety issue: No ]
• pharmacokinetics hA20 [ Time Frame: first 12 weeks, then up to 2 years ] [ Designated as safety issue: No ]
• assess efficacy [ Time Frame: 4 and 12 weeks, then every 3 months for 2 years ] [ Designated as safety issue: No ]

This study is being done to assess the safety and tolerance of different doses of humanized hA20 in patients with NHL.

• Non-Hodgkin's Lymphoma
• Lymphoma, Diffuse
• Lymphoma, Diffuse, Mixed Lymphocytic-Histiocytic

• Franck Morschhauser1*, John P Leonard2, Bertrand Coiffier3*, et.al. INITIAL SAFETY AND EFFICACY RESULTS OF A SECOND-GENERATION HUMANIZED ANTI-CD20 ANTIBODY, IMMU-106 (HA20), IN NON-HODGKINS LYMPHOMA: ASH abstract 2005.
• Morschhauser F, Leonard JP, Coiffier B Petillon M, Coleman M,. Bahkti A, Teoh N, Wegener WA, Goldenberg DM. Phase I/II result of a seoncd-generation humanized anti- CD20 antibody, IMMU-106 (.hA20), in NHL: 2006 ASCO Annual Meeting.Proceedings; 24/18S Part I of II:429s
• Morschhauser F, Leonard JP, Fayad L, Coiffier B, Petillon M, Coleman M,. Horne H, Teoh N, Wegener WA, Goldenberg DM. Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results. 2007 ASCO Annual Meeting.Proceedings; 25/18S Part I of II:449s
• Morschhauser F, Leonard JP, Fayad L, Coiffier B, Petillon MO, Coleman M, Schuster SJ, Dyer MJ, Horne H, Teoh N, Wegener WA, Goldenberg DM. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: phase I/II results. J Clin Oncol. 2009 Jul 10;27(20):3346-53. Epub 2009 May 18.
• Stein R, Qu Z, Chen S, Rosario A, Shi V, Hayes M, Horak ID, Hansen HJ, Goldenberg DM. Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and Its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin Cancer Res. 2004 Apr 15;10(8):2868-78.
• Stein R, Qu Z, Chen S, Solis D, Hansen HJ, Goldenberg DM. Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct antilymphoma activity and increases the potency of rituximab. Blood. 2006 Oct 15;108(8):2736-44. Epub 2006 Jun 15.
• Goldenberg DM, Morschhauser F, Wegener WA. Veltuzumab (humanized anti-CD20 monoclonal antibody): characterization, current clinical results, and future prospects. Leuk Lymphoma. 2010 May;51(5):747-55. Review.

Inclusion Criteria:

• Male or female, >18 years old
• Histological diagnosis of CD20+ B-cell NHL (all grades) by WHO lymphoma criteria
• Failed at least one prior standard chemotherapy regimen for NHL
• Failed rituximab treatment for relapsed NHL
• Measurable NHL disease by CT, with at least one lesion >1.5 cm in one dimension
• Adequate performance status (>70 Karnofsky scale, 0-1 ECOG) with an estimated life expectancy of at least 6 months
• Adequate hematologic status, without ongoing transfusional support (hemoglobin ≥ 10 g/dL, ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L)
• Adequate renal and hepatic function, defined as: creatinine ≤ 1.5 x Institution Upper Limit of Normal (IULN), bilirubin ≤ 1.5 x IULN, AST and ALT ≤ 2.5 x IULN
• Otherwise, <Grade 1 toxicity at study entry by NCI CTC version 2.0, including recovery from all acute toxicities incurred as a result of previous surgery, radiotherapy or chemotherapy, whether investigational or conventional.
• At least 6 months beyond previous rituximab treatment, 12 weeks beyond autologous stem cell transplant, 4 weeks beyond chemotherapy, other experimental treatments, or any radiation therapy to the index lesion(s).
• Ability to provide signed, informed consent

Exclusion Criteria:

• Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test
• Women of childbearing potential and fertile men who are not practicing or who are unwilling to practice birth control while enrolled in the study until at least 12 weeks after the last weekly hA20 infusion.
• Rituximab resistant, defined as having progressed during or within 6 months of rituximab treatment.
• Excessive toxicity to rituximab (NCI CTC Grade 3 or 4) or known to be HACA positive
• Prior radioimmunotherapy, including Zevalin or Bexxar,
• Prior therapy with other human or humanized monoclonal antibodies, unless HAHA tested and negative
• Primary CNS lymphoma, HIV lymphoma or transformed lymphoma, or presence of symptomatic CNS metastases or carcinomatous meningitis.
• Bulky disease by CT, defined as any single mass >10 cm in its greatest diameter
• Pleural effusion with positive cytology for lymphoma Known to be HIV positive, or hepatitis B or C positive
• Known autoimmune disease or presence of autoimmune phenomena.
• Evidence of infection or requiring antibiotics within 5 days.
• Corticosteroid use within 2 weeks
• Prior malignancy with less than a 5-year disease-free interval, excluding nonmelanoma skin cancers and carcinoma in situ of the cervix.
• Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of studyprocedures and follow-up examinations