Seattle Genetics has initiated a phase I/II clinical trial of vadastuximab talirine (SGN-CD33A; 33A) in combination with azacitidine (Vidaza) in patients with previously untreated myelodysplastic syndrome (MDS). 33A is an antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. Azacitidine is a hypomethylating agent (HMA) commonly used in the treatment of MDS. MDS is known to be a precursor to acute myeloid leukemia (AML), and broadly expresses CD33.

“Most newly diagnosed patients with intermediate or high risk MDS are ineligible for allogeneic stem cell transplant due to age, comorbidities or lack of appropriate donor. For these patients, novel therapies are urgently needed to prolong survival and delay disease progression into AML,” said Jonathan Drachman, M.D., chief medical officer and executive vice president, R&D at Seattle Genetics. “In our phase I AML clinical trial evaluating 33A plus HMAs (azacitidine or decitabine), we have observed encouraging tolerability and depletion of blasts from the bone marrow in many patients, and we recently presented preclinical data demonstrating synergistic activity of 33A plus HMAs. Expanding our clinical evaluation of 33A in MDS is part of a broad clinical development strategy to establish 33A as the foundation of care for patients with myeloid malignancies.”

The phase I/II, open-label, multicenter clinical trial is designed to evaluate the safety and activity of 33A administered in combination with azacitidine in patients with previously untreated International Prognostic Scoring System (IPSS) Intermediate-2 or high risk MDS. Phase I of the study will identify the recommended dose of 33A when combined with azacitidine in this patient population. The phase II portion of the trial will be a randomized, double-blind, placebo-controlled study evaluating azacitidine with or without 33A.

The primary endpoint in phase I is determination of the recommended 33A dose in combination with azacitidine. The primary endpoint in phase II is to compare the overall response rate between the two treatment arms. The secondary endpoints include evaluation of safety, best response, duration of response, progression-free survival and overall survival. The phase I/II trial will enroll approximately 130 patients at approximately 35 centers in North America.

In addition to this MDS trial, Seattle Genetics is evaluating 33A broadly across multiple lines of therapy in patients with AML, including the following ongoing trials:

• A phase I 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 Ib trial in combination with standard of care intensive chemotherapy, including cytarabine and daunorubicin, for younger fit patients with AML; and,
• A phase I/II 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.

Additionally, a phase III clinical trial to evaluate 33A in combination with HMAs in previously untreated older AML patients is planned to begin by the third quarter of 2016.