Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood. The disease starts starts in the blood stem cells, cells that are supposed to mature into different types of blood cells. According to the American Cancer Society, in 2014 more than 18,500 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults). Acute myeloid leukemia, which is slightly more common among men than among women, is generally a disease of older people and is uncommon before the age of 45. The average age of a patient with AML is about 66 years. The lifetime risk of getting AML for the average man is about 1 in 227; for the average woman the risk is about 1 in 278. Without treatment the diseases progresses very rapidly. [1] However, current therapies for acute myeloid leukemia are associated with high failure and relapse rates.

Notwithstanding the unprecedented progress in the understanding of the genetic and molecular biology of acute myeloid leukemia, so far, this increased knowledge has not been translated into significant advances in therapy.

Now a new phase Ib clinical trial investigating SGN-CD33A, a drug being developed by Seattle Genetics, in combination with standard of care chemotherapy, including cytarabine (also known as Ara-C; arabinofuranosyl cytidine, a drug that kills cancer cells by interfering with DNA synthesis) and daunorubicin (also known as daunomycin; daunomycin cerubidine, a chemotherapeutic of the anthracycline family which interacts with DNA by intercalation and inhibition of macromolecular biosynthesis) may help lead to a new, targeted, drug to help patients with newly diagnosed acute myeloid leukemia.

The same trial will also evaluate SGN-CD33A in the consolidation setting for acute myeloid leukemia, both in combination with cytarabine and as a single-agent maintenance regimen.

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SGN-CD33A is also under evaluation in an ongoing phase I dose escalation trial as a single-agent or in combination with hypomethylating agents (HMA) for the treatment of patients who have relapsed AML or have declined intensive frontline therapy. [2]

A novel approach
SGN-CD33A is a novel antibody-drug conjugate or ADC targeted to CD33. The trial drug uses the company’s newest technology. Simply stated, ADCs are monoclonal antibodies or mAbs 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 or 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.

Acute myeloid leukemia and CD33
CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage (myeloid progenitors, monocytes, granulocytes, dendritic cells and mast cells) and represents a promising target because, regardless of age, risk factors, or underlying mutational heterogeneity, it is expressed on the surface of myeloblasts in 85 to 90% of patients with AML .

Furthermore, CD33, a member of the sialoadhesion immunoglobulin superfamily which functions as a sialic acid-dependent cell adhesion molecule with carbohydrate/lectin binding activity, is absent on normal platelets, lymphocytes, erythrocytes and hematopoietic stem cells.

The anti-CD33 immunotoxin gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth), a humanized anti-CD33 monoclonal antibody conjugated with calicheamicin, a potent antitumor anthracycline antibiotic, against acute myeloid leukemia (AML) showed initial positive results. Although results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal of this agent when improved efficacy could not be demonstrated and toxicity appeared excessive, the drug confirmed that targeting CD33 holds many promises.

Photo: Clay B. Siegall, Ph.D. President, Chief Executive Officer and Chairman of the Board, Seattle Genetics, Inc.

Few therapeutic advances
“There have been few therapeutic advances for the treatment of acute myeloid leukemia in the past three decades, and there is a significant need to identify more efficacious treatment options that result in durable remissions for patients,” noted 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 acute myeloid leukemia patients from our ongoing phase I trial, as well as the preclinical data in acute myeloid leukemia models supporting combination regimens, both of which were recently presented at the Annual Meeting of the American Society of Hematology in San Francisco. 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 Ib, 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, which is the highest dose that does not cause unacceptable side effects, 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 Ib trial will enroll approximately 90 patients at multiple centers in the United States.

Clinical data from an ongoing phase I trial of SGN-CD33A in acute myeloid leukemia, presented by Eytan Stein from the Memorial Sloan-Kettering Cancer Center, New York, NY, in an oral session at the 56th Annual Meeting of the American Society of Hematology (ASH) confirms the antileukemic activity of the trial drug. [3]

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% had underlying myelodysplasia. Single-agent SGN-CD33A induced bone marrow blast clearance in 44% of evaluable patients treated across all dose levels, including 21% with a complete remission or complete remission with incomplete recovery (CR/CRi). A dose-response relationship is evolving, with 77% of patients treated at doses greater than or equal to 40 micrograms per kilogram achieving at least 50% blast reduction. Adverse events were generally manageable and associated with underlying myelosuppression.

Updated results of the phase Ib trials with SGN-CD33A are expected in 2015 and 2016.