Safety and Efficacy Study of an Anti-CD20 Monoclonal Antibody (AME-133v) to Treat Non-Hodgkin's Lymphoma

Open-Label, Multicenter, Phase 1/2 Dose-Escalation Study of AME-133v (LY 2469298), Administered Intravenously in Four Weekly Doses, in Subjects With CD20+ Follicular Relapsed or Refractory Non-Hodgkin's Lymphoma

This study is designed to provide evidence of the safety and a preliminary understanding of the efficacy of AME 133v.

The protein engineering of AME-133v is hypothesized to result in an anti-CD20 therapy with greater potency and efficacy in all patients, but particularly in genetically defined subpopulations that respond poorly to rituximab because they express a low affinity version of the Fc receptor on their immune effector cells. A monoclonal antibody that has increased binding for this receptor should be more effective in stimulating effector cell killing and thus improve response to the antibody.

Inclusion Criteria:

To be included in the study protocol, subjects have to meet all of the following criteria.

• Have morphologically confirmed diagnosis of CD-20+ follicular B-cell non-Hodgkin's lymphoma;

• Have the low affinity form of FcγRIIIa (F/F or F/V at position 158) as determined by FcR genotyping;

• Have measurable disease. Measurable masses (such as enlarged lymph nodes) must have a clearly defined bi-dimensional diameter of at least 1.5 x 1.5 cm on physical examination or ≤ 1.5 cm in one of the dimensions by CT, MRI, or plain radiograph;

• Have received prior treatment with chemotherapy given without rituximab; OR, Have not relapsed or progressed within 120 days (inclusive) of the last infusion of rituximab;

• Be 18 years of age or greater;

• Have a negative pregnancy test, if relevant. Women of childbearing potential (not postmenopausal for at least one year and not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study. To do this, they must agree to use a medically acceptable contraceptive regimen;

• Have a performance status of 0 to 2 on the ECOG performance scale;

• Have adequate hematopoietic, renal, and hepatic function defined as:

  1. Absolute neutrophil count greater than 1,500/mm³;
  2. Platelet count greater than 75,000/mm³;
  3. Hemoglobin at least 8 g/dL;
  4. Serum creatinine ≤ 1.5x upper limit of normal;
  5. Total bilirubin ≤ 1.5x upper limit of normal;
  6. ALT ≤ 1.5 x upper limit of normal;
  7. Alkaline phosphatase ≤ 1.5x upper limit of normal.

• No evidence of hepatitis B or C infection (no detectable HBV DNA or HCV RNA);

• Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, or other investigational therapy for at least 30 days prior to study enrollment;

• Have discontinued all high-dose corticosteroid therapy at least 30 days prior to study enrollment (≤ 10 mg/day of Prednisone or equivalent is allowable);

• Have life expectancy of more than 3 months;

• Be able to give written informed consent.

Exclusion Criteria:

Subjects with any of the following exclusions are not allowed to participate in the study.

• Allergy to monoclonal antibodies or any of the study drug components;
• Concurrent malignancy that could complicate interpretation of response evaluation, including any histologic evidence of diffuse B-cell lymphoma. Non-melanoma skin cancer and carcinoma in situ of the cervix are not exclusions;
• Significant cardiac disease (e.g. NYHA CHF of class III or IV, history of MI within one year prior to study Day 1, unstable angina, uncontrolled hypertension, clinically significant cardiac arrhythmia (CTCAE Grade 2 or higher), or clinically significant baseline ECG or MUGA abnormality.
• Positive test for serum cardiac troponins (cTnI or cTnT assay; special processing required, and the same assay must be used throughout the study; see Study Reference Manual)
• Active infection requiring oral or i.v. antibiotics;
• Administration of blood transfusions or red blood cell growth factors within 10 days preceding enrollment into the protocol;
• Administration of white cell growth factors within 28 days preceding enrollment into the protocol;
• Concomitant nonmalignant disease(s) which could interfere with implementation of the protocol, make the study results difficult to interpret, or which represent additional safety risks;
• History of HIV-associated non-Hodgkin's lymphoma.