Date: 2014-12-08
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, being held December 6-9 in San Francisco, CA
Company: Seattle Genetics (USA - WA)
Product: SGN-CD33A
Action
mechanism: antibody drug conjugate. 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 the first ADC utilizing an engineered cysteine antibody (EC-mAb) and pyrrolobenzodiazepine (PBD) dimer to be advanced into the clinic. 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 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. 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 agent 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.
Disease: acute myeloid leukemia
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On December 8, 2014, Seattle Genetics presented data from an ongoing phase 1 clinical trial evaluating SGN-CD33A, an antibody-drug conjugate (ADC) in development for the treatment of acute myeloid leukemia (AML), at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in San Francisco, CA December 6-9, 2014. Data were reported from 56 evaluable AML patients with a median age of 75 years and predominantly intermediate or adverse cytogenetic risk. Of the 56 patients, 43 percent had received intensive therapy and 57 percent had declined intensive therapy. More than 50 percent of patients had evidence of underlying myelodysplasia.The primary endpoints of the trial are the estimation of the maximum tolerated dose and evaluation of the safety of SGN-CD33A. In addition, the trial is evaluating anti-leukemic activity, pharmacokinetics, progression-free survival and overall survival in patients with CD33-positive AML. Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with CD33-Positive Acute Myeloid Leukemia (AML) (Abstract #623): Key findings presented by Dr. Stein include: Of the 52 evaluable patients treated across all dose levels, the best clinical response by investigator included 11 patients (21 percent) with a complete remission or complete remission with incomplete recovery (CR/CRi). An additional 12 patients (23 percent) achieved a morphologic leukemia free state. Data suggest an emerging dose-response relationship with rapid and marked decreases in bone marrow blasts. Of the 17 response-evaluable patients treated at 40 micrograms per kilogram (mcg/kg), five patients (29 percent) achieved a CR/CRi. At last follow-up, 12 of 18 patients (67 percent) treated at this dose level remained alive. Ten patients treated at this dose level were elderly and had declined intensive therapy, of which four patients (40 percent) achieved CR/CRi. Among patients treated at the 40 mcg/kg dose level or higher, 77 percent (17 of 22) had a 50 percent or more reduction in bone marrow blasts. For CR/CRi patients, median time to neutrophil count recovery was 6.7 weeks and median time to platelet count recovery was 12 weeks. The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were febrile neutropenia (32 percent), fatigue (20 percent) and low blood platelet count (16 percent); the most common post-baseline Grade 3 or 4 laboratory abnormalities were low blood neutrophil count (98 percent), low blood leukocyte count (97 percent) and low blood platelet count (87 percent). The 30-day mortality rate was two percent, with no treatment-related deaths occurring during that time.The maximum tolerated dose (MTD) has not been reached and dose exploration is continuing, including combination cohorts with hypomethylating agents. SGN-CD33A in Combination with Cytarabine or Hypomethylating Agents Demonstrate Enhanced Anti-leukemic Activity in Preclinical Models of AML (Abstract #3739) A preclinical analysis evaluated the activity of SGN-CD33A in combination with therapies commonly used to treat AML, including cytarabine and hypomethylating agents, in multi-drug resistant AML models. Data presented in a poster presentation by May Sutherland, Ph.D., Seattle Genetics, demonstrated enhanced anti-leukemic activity observed with the combination of SGN-CD33A and cytarabine or hypomethylating agents as well as synergistic mechanisms of action and anti-tumor activity. In addition, use of hypomethylating agents increased CD33 levels on AML cells.
The SGN-CD33A phase 1 clinical trial is ongoing to define an optimal monotherapy dose and schedule for future trials.
