Study Start Date: 08/01/2011
Study End Date: 12/31/2011

NBD peptide as an adjunct therapy for the treatment of canine diffuse large B cell lymphoma
Multicentric diffuse large B cell lymphoma is the most common hematopoietic cancer in dogs and is currently treated using a combination of chemotherapeutic agents, which inhibit cell division and induce cell death. In most cases chemotherapy induces clinical remission in 65-96% of patients. However, 85-90% of patients relapse with lethal, drug-resistant lymphoma within 6 to 9 months of diagnosis. The NF-kappaB family of transcription factors controls genes that promote lymphocyte proliferation and survival. In health, the intracellular pathway leading to NF-kappaB activation is highly regulated, being activated only when engaged by certain cell surface receptors. We have recently identified aberrant, constitutive NF-kappaB activity in malignant B cells from dogs with DLBCL and have shown that inhibition of this pathway leads to malignant B cell death. Similar findings have been reported for human patients with DLBCL and it is widely recognized in humans that persistent activation of the NF-kappaB signaling pathway in malignant cells contributes to their enhanced proliferation, survival and resistance to chemotherapeutic drugs. In this clinical trial we are building on our previous findings and performing a phase I dose escalation study to determine the safety and biologically effective dose of NBD peptide administered intravenously to dogs with either newly diagnosed DLBCL or relapsed DLBCL. This trial aims to build the rationale for the use of this selective NF-kB inhibitor as an adjunct agent to increase the sensitivity of cancer cells to chemotherapy. It is anticipated that this work will provide the preliminary data necessary to initiate a phase II randomized, placebo controlled clinical trial to evaluate NF-kB inhibition as an adjunct to chemotherapy to enhance clinical response during rescue therapy.

Study Design:
Prospective

Sample Size:
9-18 dogs

Inclusion Criteria:

• Dogs with a confirmed diagnosis of B cell lymphoma (Stage 3 and above, substage a only)
• Newly diagnosed or relapsed cases are eligible
• Performance status = 0 or 1 Life expectancy >1 month
• Dogs have to be treated at University of Pennsylvania

Exclusion Criteria:

• Other types of heart disease, acquired or congenital. Significant organ related or systemic disease
• Patients that have received chemotherapy within the last 3 weeks (eligible after this period)
• Patients that have received prednisone within the last week (eligible adter this period)
• Creatinine and Total Bilirubin > 1.5x upper limits of normal
• HCT <100,000

Study Controls:
NA

Study Endpoints:
Primary end-points:

1. Inhibition of NF-kappaB activity (as defined by reductions in phosphorylation of IKK and IkBalpha) in malignant lymphocytes
2. Evaluation of NBD peptide pharmacokinetics following intravenous administration

1. Disease free interval
2. Time to progression

Costs/Reimbursments
Participants will receive blood work, immnophenotyping, histopathology, antibiotics, study drug and first dose of chemotherapy free of charge.

Full Disclosure information:

• The study is funded by a grant from NIH.
• The investigator does not have a conflict of interest.
• The study will be published if results are negative

Date published: 11/01/2011