SGN-CD33A Targets AML by Directly Delivering Toxins
January 2014 | eNews
Acute myeloid leukemia (AML) is a blood malignancy characterized by the proliferation of immature white blood cells, with a concurrent deficiency of normal blood cells. Even with treatment, AML has a poor prognosis, with five-year survival rates ranging from 60% in those with favorable-risk disease to as low as 5% in patients with poor-risk features.
An Antibody-based Therapy for AML
AML is currently treated with conventional chemotherapies such as anthracyclines and cytarabine. Amir Fathi, MD (MGH), is exploring a novel approach to improving outcomes for patients with AML as the principal investigator of a trial designed to evaluate SGN-CD33A, an antibody-drug conjugate.
While up to 70% of patients go into remission after initial treatment of AML, most experience relapse, thought to be associated with the development of mutations during therapy. Relapse is what accounts for the poor survival rates in patients with this disease, says Fathi. "As opposed to conventional chemotherapies, which are indiscriminate killers of rapidly dividing cells, these drugs are thought to target the leukemic cells, and that is why they are quite interesting."
In the last decade, several antibody-based therapies have been evaluated in a range of hematologic malignancies, says Fathi. Initially, the agents used were “naked” antibodies that targeted proteins on malignant cells. But newer generation antibodies are bound to toxins or chemotherapeutic agents, and allow the antibody to deliver the toxin directly into the cell.
SGN-CD33A targets CD33, a protein that is expressed on most AML cells. The toxic part of the SGN-CD33A molecule is a potent cell-killing agent called a pyrrolobenzodiazepine (BPD), and this is linked to an antibody directed to CD33. BPD is thought to kill cells by crosslinking DNA and interrupting cell division.
Antibody-based therapies targeting CD33, such as gemtuzumab ozogamicin, have also been evaluated in AML and have demonstrated some activity; thus, CD33 remains a valid drug target, and SGN-CD33A may help improve upon these results.
The main goal of this Phase 1 trial is to assess the safety and tolerability of SGN-CD33A. "Once an established safe and tolerable dose is determined, more advanced phases of clinical investigation will be undertaken to better assess efficacy and eventually improve upon the current standard of care," explains Fathi.
The Phase I trial is designed to evaluate SGN-CD33A in patients with AML. Patients must have achieved a complete response lasting for at least 12 weeks followed by a relapse and not have received more than one non-myeloablative regimen after relapse, or, if they declined high-dose induction/consolidation therapy, they must have received no more than one palliative therapy.
Previous nonclinical studies have demonstrated targeted cell killing in vitro and in vivo, and the expected toxicity profile has been adequately characterized to select a starting dose and aid in the appropriate monitoring of patients. Patients will receive SGN-CD33A at a dose based on actual body weight (to the nearest tenth of a kilogram) assessed on Day 1 of 3-week cycles. The maximum tolerated dose will be determined by observing the dose-limiting toxicities.
Phase I Trial
Title: A phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia
Principal Investigator: Amir Fathi, MD (MGH)
NIH Trial Number: NCT01902329
DF/HCC Protocol Number: 13-321
More Information: The trial is ongoing and recruiting patients. Find more information at ClinicalTrials.gov.
— Emma Nichols