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Earlier today Seattle Genetics, a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer,  confirmed that it had started a phase I/II clinical trial of vadastuximab talirin, also known as SGN-CD33A, in patients with relapsed or refractory acute myeloid leukemia, also called acute myelocytic leukemia or AML.

The new clinical trial is designed to evaluate novel drug as a monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant (alloSCT). Vadastuximab talirine will also be investigated for use as maintenance therapy following transplant. Trial is based on anti-leukemic activity observed in ongoing phase I clinical trials evaluating vadastuximab talirine in AML

Vadastuximab talirine is a novel, investigational, antibody-drug conjugate or ADC targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on almost all AML cells, regardless of subtype, cytogenetic abnormality, or underlying mutations.

The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells. Vadastuximab talirine is being evaluated in ongoing phase I and phase I/II clinical trials for patients with acute myeloid leukemia, also called acute myelocytic leukemia or AML.

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An aggressive cancer
Acute myeloid leukemia, is an aggressive type of cancer of the bone marrow (the soft inner part of the bones) and blood that starts in the cells that are supposed to mature into different types of blood cells. It is not a single disease, but a group of related diseases. Patients with different subtypes of AML can have different outlooks and responses to treatment. However, without treatment the disease progresses ver rapidly. Today, the main treatment for AML is chemotherapy, sometimes followed by a stem cell transplant.

According to the American Cancer Society, more than 20,500 new cases of AML (mostly in adults) were diagnosed in 2015 and nearly 10,500 deaths occurred as a result of the disease, most of them adults.[1]

Improving treatment
Scientists are trying to improve the number of treatments by looking to find the most effective combination of chemotherapy therapeutic drugs as well as other approaches while avoiding unwanted adverse effects. But the treatment outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and new treatments are urgently needed.

One novel strategy being explored includes antibodies and their drug conjugates, especially antibodies targeting CD33.  Data from from gemtuzumab ozogamicin (Mylotarg®; Pfizer) demonstrate CD33 target validity and activity in patients with AML, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multidrug resistance.

Especially in older individuals outcomes are considered poor. One reason is a lower tolerance for the intensive chemotherapy required to achieve morphologic remission and because of a higher prevalence of chemoresistance (multidrug resistance [MDR]).

“Relapsed and refractory acute myeloid leukemia, or AML, remains among the most challenging unmet needs in cancer, and there continues to be little success in treating AML patients utilizing conventional salvage therapies,” explained Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “Our strategy with this trial is to evaluate the potential for vadastuximab talirine to increase the percentage of patients who have no detectable leukemic cells prior to allogeneic transplant. Data suggest that patients who test negative for minimal residual disease prior to transplant are less likely to relapse. Separately, we will evaluate the potential for SGN-CD33A to maintain remissions after allogeneic transplant.”

Trial design
The phase I/II, open-label, multi-center, clinical trial is a two-part (A and B) study designed to evaluate the safety and activity of SGN-CD33A administered in patients with relapsed chemotherapy-resistant AML. Part A of the study will examine SGN-CD33 as cytoreduction pre-conditioning and Part B will evaluate SGN-CD33A in post-alloSCT as a maintenance regimen. Each part will consist of a phase I safety evaluation followed by a phase II expansion for activity. Parts A and B will enroll concurrently.

The primary endpoints in phase I are determination of the maximum tolerated dose (MTD) and the safety and tolerability profiles of vadastuximab talirine in both pre- and post-alloSCT settings. The primary endpoints in phase 2 are to evaluate the one-year survival rates of patients treated with vadastuximab talirine at the recommended dose pre- and post-alloSCT; to assess the rate of minimal residual disease negativity; and to further assess the safety and tolerability of vadastuximab talirine at the recommended dose. The secondary endpoints include assessments of best response on study treatment, duration of response and overall survival. The two-part, phase 1/2 trial will enroll approximately 100 patients at multiple centers in the United States.

More research
Vadastuximab talirine is also under evaluation in two other ongoing clinical trials including a phase I dose escalation trial as a single-agent or in combination with hypomethylating agents (HMAs) for the treatment of patients who have relapsed AML or have declined intensive frontline therapy; and a phase Ib clinical trial in combination with standard of care intensive chemotherapy, including cytarabine and daunorubicin, for younger fit patients with newly diagnosed AML.

American Society of Hematology meeting
The phase I clinical data for vadastuximab talirine in AML as monotherapy and in combination with HMAs will be presented in two oral sessions (Abstracts #324 and #454) and preclinical data supporting HMA combination strategy will be presented in a poster session (Abstract #3785) at the upcoming American Society of Hematology Annual Meeting from December 5-8, 2015 in Orlando, FL.

With more than 15 years of experience and innovation, Seattle Genetics is the leader in developing antibody-drug conjugates. ADCs are monoclonal antibodies that are designed to selectively deliver cell-killing agents to 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.

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