On December 18, 2014 Seattle Genetics reported the initiation of a phase 1b clinical trial of SGN-CD33A in combination with standard of care chemotherapy, including cytarabine and daunorubicin, for patients with newly diagnosed acute myeloid leukemia (AML) (Press release Seattle Genetics, DEC 18, 2014, View Source;p=RssLanding&cat=news&id=2000668 [SID:1234501213]). The trial will also evaluate SGN-CD33A in the consolidation setting for AML, both in combination with cytarabine and as a single-agent maintenance regimen. SGN-CD33A is a novel antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology. CD33 is expressed on most AML cells regardless of subtype, cytogenetic abnormality or underlying mutational heterogeneity. SGN-CD33A is also under evaluation in an ongoing phase 1 dose escalation trial as a single-agent or in combination with hypomethylating agents for the treatment of patients who have relapsed AML or have declined intensive frontline therapy.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"There have been few therapeutic advances for the treatment of AML in the past three decades, and there is a significant need to identify more efficacious treatment options that result in durable remissions for patients," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "We are encouraged by the single-agent activity of SGN-CD33A in AML patients from our ongoing phase 1 trial, as well as the preclinical data in AML models supporting combination regimens, both of which were recently presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Based on these data, we are expanding the evaluation of SGN-CD33A to include combination with standard of care chemotherapy in frontline and consolidation AML settings."
The study is a phase 1b, open-label, multi-center, dose-escalation clinical trial designed to evaluate SGN-CD33A administered in combination with frontline standard of care regimens for induction (cytarabine and daunorubicin) and/or consolidation (cytarabine). In addition, the study will evaluate single-agent SGN-CD33A as a maintenance regimen. The primary endpoints are determination of the maximum tolerated dose and safety profile of SGN-CD33A in these settings. In addition, the trial will evaluate anti-leukemic activity, pharmacokinetics, progression-free survival and overall survival. The phase 1b trial will enroll approximately 90 patients at multiple centers in the United States.
Clinical data from an ongoing phase 1 trial of SGN-CD33A in AML were presented in an oral session at the 2014 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #623). In this dose-escalation study, 56 patients had been enrolled. Patients were primarily older (median age 75 years) with relapsed AML, predominantly with intermediate or adverse cytogenetic risk and 55 percent had underlying myelodysplasia. Single-agent SGN-CD33A induced bone marrow blast clearance in 44 percent of evaluable patients treated across all dose levels, including 21 percent with a complete remission or complete remission with incomplete recovery (CR/CRi). A dose-response relationship is evolving, with 77 percent of patients treated at doses greater than or equal to 40 micrograms per kilogram achieving at least 50 percent blast reduction. Adverse events were generally manageable and associated with underlying myelosuppression.
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 antitumor activity.
SGN-CD33A is comprised of three parts: A cysteine-engineered anti-CD33 antibody enabling uniform site-specific conjugation, a cleavable dipeptide linker that is highly stable in circulation, and a pyrrolobenzodiazepine (PBD) dimer that binds DNA with high intrinsic affinity. PBD dimers are a class of DNA-crosslinking agents significantly more potent than systemic chemotherapeutic drugs. Seattle Genetics has selected and optimized specific PBD molecules for its proprietary use in ADCs. In addition, SGN-CD33A employs a novel linker system and proprietary, site-specific conjugation technology (EC-mAb) that allows uniform drug-loading of the cell-killing PBD dimer to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its cytotoxic agent upon internalization into CD33-expressing cells.
For more information about the trial, including enrolling centers, please visit www.clinicaltrials.gov.