Results from Phase I Trial with SGN-CD19A Shows Encouraging Anti-tumor Activity in Non-Hodgkin Lymphoma

Results from an interim phase I clinical trial presented at the 50th Annual Meeting of the American Association of Clinical Oncology (ASCO), being held May 30 – June 3, 2014 in Chicago, Ill, shows that SGN-CD19A (Seattle Genetics, Inc, Bothell, WA 98021, USA), an antibody-drug conjugate or ADC in development for the treatment of B-cell malignancies, offers encouraging anti-tumore activity in patients with Non-Hodgkin Lymphoma (NHL).[1]

Lymphoma is a hematological (blood) cancer that begins in cells of the immune system. The two main forms of lymphoma are Hodgkin lymphoma (HL), which is marked by the presence of a type of cell called the Reed-Sternberg cell, and non-Hodgkin lymphoma (NHL). Lymphoma occurs when lymphocytes, a type of white blood cell, grow and multiply uncontrollably. When unchecked, these cancerous lymphocytes travel to various parts of the body, including the lymph-nodes, spleen, bone marrow, blood, or other organs, where they form tumors.

Diffuse large B-cell lymphoma or DLBCL is the most common form of NHL, accounting for up to 30% of newly diagnosed cases in the United States. DLBCL is an aggressive or fast-growing lymphoma and arises both in lymph nodes as well as outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Although DLBCL is the most common form of NHL, there are several other subtypes, including indolent (slow-growing) NHL that behave and respond to diferently to treatment.

Lymphoma, including HL and NHL, represents approximately 5% of all cancers in the United States. Based on data from the American Cancer Society,  nearly 70,000 new cases of NHL and 9,300 new cases of Hodgkin lymphoma are estimated for 2014.

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…interim phase I data in aggressive non-Hodgkin lymphomas (NHL) along with previous phase I data in acute lymphoblastic leukemia (ALL), demonstrates that SGN-CD19A has encouraging antitumor activity with multiple complete remissions in a patient population with significant unmet needs…

Targeted Approach
The trial drug SGN-CD19A is an Antibody-drug Conjugate or ADC targeting CD19, a protein expressed on B-cell malignancies ALL and NHL, including DLBCL. Using Seattle Genetics’ proprietary technology, SGN-CD19A is comprised of an anti-CD19 monoclonal antibody linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin F or MMAF. An antibody-drug Conjugates is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. In this process, ADCs harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

Preclinical data presented at the 2011 American Association for Cancer Research Annual Meeting demonstrated that SGN-CD19A effectively binds to target cells, internalizes and induces potent cell-killing activity and durable tumor regressions at low doses in multiple preclinical cancer models. SGN-CD19A is being evaluated in two ongoing phase I clinical trials for patients with B-cell ALL and aggressive NHL.

Study results
Data were reported from 37 patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL), including 32 patients with diffuse large B-cell lymphoma (DLBCL), four patients with mantle cell lymphoma (MCL) and one patient with Grade 3 follicular lymphoma. The median age of patients was 65 years and the median number of prior systemic therapies was two, with 10 patients (27%) having received a prior autologous stem cell transplant. Among enrolled patients, eight percent were primary refractory, 54% were refractory to their last treatment and 38% had relapsed following a response to their last treatment.

Primary Endpoints
The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of SGN-CD19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients receive a single dose of SGN-CD19A on an every 3-week basis. Key findings included:

• No dose limiting toxicity was observed in the first cycle for any patients. Adverse events were observed in the 6 milligrams per kilogram (mg/kg) dosing regimen after the first cycle, therefore enrollment was discontinued. The 3, 4 and 5 mg/kg cohorts are being expanded, and the trial continues to enroll.
• At the time of data analysis, of the 37 patients treated across all dose levels, the objective response rate observed was 30% (11 patients).
• Six patients (16%) achieved a complete remission, five (14%) achieved a partial remission, 13 (35%) had stable disease and 13 (35 percent) had progressive disease as best response.

The clinical trial is ongoing with nine of the 37 patients (24%) remaining on treatment and new patients continuing to be enrolled.[2][3]

Adverse events
The most common adverse events of any grade occurring in more than 30 percent of patients were blurred vision (51%), fatigue (38%), dry eye (35%), constipation (30%) and keratopathy (30%). Grade 3 or higher adverse events observed in two or more patients included blurred vision (six patients), keratopathy (three patients), low platelet count (three patients) and anemia (three patients).

Final results
Commenting on the data, Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics, noted: “We continue to make strong progress advancing our proprietary pipeline programs, with SGN-CD19Autive Vice President, Research and Development at Seattle Genetics. The interim phase I data in aggressive non-Hodgkin lymphomas presented at ASCO, along with previous phase I data in acute lymphoblastic leukemia, demonstrate that SGN-CD19A has encouraging antitumor activity with multiple complete remissions in a patient population with significant unmet needs. The safety profile of SGN-CD19A is generally manageable with a notable absence of significant neuropathy or bone marrow suppression, which may enable future clinical trials with novel combination regimens. We look forward to final results from this ongoing phase I clinical trial to inform future SGN-CD19A program development plans.”