A phase III study called CASCADE, designed to evaluate Seattle Geneticsvadastuximab talirine (SGN-CD33A; 33A) in combination with azacitidine (Vidaza) or decitabine (Dacogen) has been initiated in older patients with newly diagnosed acute myeloid leukemia (AML).

Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. This type of cancer starts in the cells that are supposed to mature into different types of blood cells. As such, AML starts in the bone marrow, the interior part of bones where new blood cells are made,  and quickly move into the blood. According to the American Cancer Society, in 2016 approximately 20,000 new cases of AML will be diagnosed and nearly 10,500 deaths will occur from AML.

Significant unmet need
“Acute myeloid leukemia, or AML, is a devastating disease representing a significant unmet medical need. It impacts approximately 20,000 people in the U.S. each year, with few effective treatment options. Older AML patients have a particularly poor prognosis as the majority have high risk disease characteristics and a median survival of ten months or less with available therapies,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“We have a robust development strategy, with several ongoing clinical trials across multiple lines of therapy in myeloid malignancies to explore 33A as a treatment option broadly in AML. This pivotal phase 3 CASCADE trial is a significant corporate milestone and an important step in our goal to improve outcomes for AML patients,” Siegall added.

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Novel treatment options
Vadastuximab talirine is an antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked via a proprietary site-specific conjugation technology, to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer.

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.

These targeted drugs are designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells.  In this way, the drug is selectively delivered as a 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 antitumor activity.

CD33 is expressed on leukemic blasts in nearly all AML patients and expression is generally consistent regardless of age, cytogenetic abnormalities or underlying mutations. Azacitidine and decitabine are hypomethylating agents (HMAs) commonly used in the treatment of older AML patients. CD33 is also expressed on MDS blast cells.

The phase III CASCADE study is a randomized, double-blind, placebo-controlled, global clinical trial. It is designed to evaluate if 33A in combination with azacitidine or decitabine can extend overall survival compared to azacitidine or decitabine alone in older patients with newly diagnosed AML. Patients will be randomized on a 1:1 ratio to be treated with an HMA plus 33A or an HMA plus placebo. The secondary endpoints include the comparison of composite complete remission rate (complete remission and complete remission with incomplete hematologic recovery; CR/CRi), event-free and leukemia-free survival, duration of response, safety, and 30- and 60-day mortality rates. The phase 3 trial will enroll approximately 500 patients globally.

Interim results
Interim results from the ongoing phase I study evaluating 33A in combination with HMAs in frontline AML and as monotherapy in primarily relapsed AML were presented at the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition. Data from the phase 1 33A combination trial demonstrated that 15 of 23 (65 percent) evaluable patients achieved CR/CRi. At a median follow-up of 7.7 months, median survival had not yet been reached, and 72 percent of patients remained alive and on study.

Updated data from the ongoing phase 1 study of 33A in combination with HMAs will be presented in an oral presentation at the 2016 European Hematology Association (EHA) Congress taking place June 9 – 12, 2016, in Copenhagen, Denmark.

Additional trials
In addition to the phase III CASCADE trial, Seattle Genetics is evaluating 33A broadly across multiple lines of therapy in patients with AML and myelodysplastic syndromes (MDS), including the following ongoing trials:

  • A phase 1 trial of 33A monotherapy and in combination with HMAs in AML patients who have relapsed/declined intensive frontline therapy or are newly diagnosed;
  • A phase 1b trial in combination with standard-of-care intensive chemotherapy (7+3), consisting of cytarabine and daunorubicin, for younger fit patients with AML;
  • A phase 1/2 trial in patients with relapsed or refractory AML evaluating 33A monotherapy as a pre-conditioning regimen prior to an allogeneic stem cell transplant and also for use as maintenance therapy following transplant; and,
  • A phase 1/2 trial of 33A in combination with azacitidine in patients with previously untreated MDS.

Data Presented at the 2015 American Society of Hematology Annual Meeting Demonstrated Encouraging Anti-leukemic Activity and Support Advancing 33A into a Registrational Trial.  Additional Phase I data will be featured in an oral presentation during the upcoming at the European Hematology Association Congress in June 2016.

Last Editorial Review: May 25, 2016

Featured Image: Leukemia cells and scienctist testing in laboratoryCourtesy: © Fotolia. Used with permission.

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