Interim phase I clinical data from SGN-CD19A (Seattle Genetics), an antibody-drug conjugate or ADC in development for the treatment of B-cell malignancies, including acute lymphoblastic leukemia (ALL), were presented at the 55th annual meeting of ASH?, the American Society of Hematology, being held in New Orleans, Louisiana, USA, from December 7 – 10, 2013.

Acute lymphoblastic leukemia, also called acute lymphocytic leukemia or ALL, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. In ALL, lymphoblasts, which are malignant, immature white blood cells, multiply and crowd out normal cells in the bone marrow. ALL is the most common type of cancer in children. According to the American Cancer Society, approximately 6,000 people were diagnosed with ALL during 2012 and more than 1,400 died from the disease. There are a number of ongoing clinical trials designed to help patients with the disease. Among these, trials with ADCs are showing exciting treatment results.

What are ADCs

ADCs like SGN-CD19A, are monoclonal antibodies linked to a cytotoxic agents and are designed to selectively kill tumor cells. Drugs in this class are designed to be stable in the bloodstream and to only release its cytotoxic agent upon internalization into tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing anti-tumor activity. [1]

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The trial drug SGN-CD19A is an antibody-drug conjugate targeting CD19, a protein expressed uniformly on almost all B-cell malignancies, linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin F (MMAF).

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Preclinical data

Preclinical data presented at the 2011 American Association for Cancer Research (AACR) 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 non-Hodgkin lymphoma.

The results of this trial are also encouraging. ?The phase I trial evaluating SGN-CD19A has demonstrated encouraging early antitumor activity and a generally well-tolerated safety profile among heavily pretreated patients with acute lymphoblastic leukemia and very aggressive types of lymphoma. In addition, multiple complete remissions have been observed in a parallel phase I study evaluating SGN-CD19A in aggressive non-Hodgkin lymphoma. Dose-escalation is ongoing in both phase I clinical trials, and we plan to report additional data during 2014,? noted Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Technology platform

With over a decade of experience and knowledge in ADC innovation, Seattle Genetics is the leader in developing ADCs. Industry wide, there are currently more than 50 antibody-drug conjugates type drugs in clinical development – ranging from preclinical to phase III. Eighteen of these drug candidates are utilizing Seattle Genetics? proprietary ADC technology platform.

Study results
The initial data included 16 adult patients and four pediatric patients with relapsed or refractory B-lineage ALL and highly aggressive lymphoma, including B-cell lymphoblastic lymphoma (B-LBL) and Burkitt lymphoma. The median age of adult patients was 46 years and the median number of prior systemic therapies was two, with six patients (38%) having received a prior allogeneic stem cell transplant. The median age of pediatric patients was 14 years and the median number of prior systemic therapies was three, with two patients (50%) having received a prior allogeneic stem cell transplant.

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 designed to evaluate antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients receive SGN-CD19A on days one and eight of every 21-day cycle. Key findings presented by Uma Borate, MD, assistant professor at the University of Alabama Devision of Hematology and Oncology, in Birmingham, AL, included:

  • At the time of data analysis, the maximum tolerated dose had not yet been reached. Enrollment and dose escalation are ongoing;
  • Of the 16 adult patients treated across all dose levels, three (19%) achieved a complete remission or complete remission with incomplete platelet recovery, eight (50%) had resistant disease with clinical benefit or stable disease and five (31 percent) had progressive disease;
  • At dose levels greater than 1.0 milligram per kilogram (mg/kg), eight of 10 adult patients had clinical benefit, consisting of complete remission, complete remission with incomplete platelet recovery, resistant disease with clinical benefit or stable disease;
  • Of the four pediatric patients, one patient had resistant disease with clinical benefit, one had resistant disease without clinical benefit, one had progressive disease and one was unevaluable.

Adverse events —

The most common adverse events of any grade occurring in adult patients were fever (56 percent), nausea (44 percent), chills (38%), fatigue (38%), blurred vision (38% and vomiting (38%). Adverse events seen in at least two pediatric patients (50 percent or more) were vomiting (three patients) and abdominal pain, cough, shortness of breath, nausea and fever (two patients each).

So far, the interim study results support Seattle Genetics? ongoing evaluation of SGN-CD19A as a treatment for B-cell malignancies.

For more information:

[1] What are ADCs ADC Review/Journal of Antibody-drug Conjugates [Article]

[2] A First-in-Human Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Acute Leukemia and Highly Aggressive Lymphoma (Abstract #1437)

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