CD33 is expressed on myeloblasts in approximately 90 percent of acute myeloid leukemia (AML) cases – regardless of patient age, prior therapies, or mutational heterogeneity – making it a promising target for treatment. According to results from a phase I trial presented at the 2015 ASH Annual Meeting, a novel CD33-directed monoclonal antibody, SCN-CD33a, demonstrated anti-leukemic activity in newly diagnosed and relapsed AML patients.
Anthony S. Stein, MD, from City of Hope National Medical Center in Duarte, California, presented the findings of the dose-escalation study, which evaluated the agent’s safety, tolerability, pharmacokinetics, and anti-leukemic activity.
At the time of study presentation, 87 patients (62 percent male) had been treated with SGN-CD33A. Patients had a median age of 74 years (range = 27-89 years). Only those with CD33-positive AML were eligible for study inclusion, and patients had either relapsed disease following first complete remission (CR) of more than three months (n=34), or had declined conventional induction/consolidation therapy (n=52).
Forty of these patients received prior low-intensity therapies with one or two agents – primarily hypomethylating agents.
Most patients had intermediate stage I-II (51%) or adverse (31%) risk, according to European Leukemia Network classification, and 54 percent of patients had evidence of underlying myelodysplasia.
SGN-CD33A monotherapy was administered intravenously every three weeks for up to two cycles, followed by an optional low-dose maintenance treatment for patients who achieved CR or CR with incomplete blood count recovery (CRi). Dose levels ranged from 5 to 60 mcg/kg (n=75) and also included fractionated dosing of 20 mcg/kg on day 1 and day 4 (n=12) of each cycle.
Investigators observed six dose-limiting toxicities in the dose-escalation cohorts: two cases of grade 4 bone marrow failures (at 40 and 60 mcg/kg); two cases of grade 3 mucositis (at 50 mcg/kg and at fractionated 20+20 mcg/kg); one case of grade 3 pulmonary embolism (20 mcg/kg), and one case of grade 5 sepsis (50 mcg/kg).
The most common grade ≥3 adverse events (AEs) were febrile neutropenia (69%), thrombocytopenia (29%), and anemia (23%). Other common treatment-emergent AEs included fatigue (48%), decreased appetite (28%), constipation, diarrhea, dyspnea, nausea (26% each), and peripheral edema (25%). Patients treated with SGN-CD33A at doses higher than 40 mcg/kg and in the fractionated dosing cohort experienced increased myelosuppression, including febrile neutropenia (68%) and sepsis (26%).
“AEs were generally manageable, and often were associated with underlying myelosuppression,” Dr. Stein reported. The rate of 30-day mortality was low at six percent.
Response was assessed according to International Working Group criteria. CRi (CR with incomplete recovery of blood counts) required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL.
Twenty-one patients in the 40 mcg/kg dose cohort were evaluable for efficacy. Median overall survival in patients treated at this dose was 10 months, with 17 patients alive at the data cut-off point. Best clinical responses were CR in three patients, CRi in four patients, and morphologic leukemia-free state in five patients. “SGN-CD33A has demonstrated favorable anti-leukemic activity, with 33 percent of study patients achieving a CR/CRi at the 40 mcg/kg dose level,” the authors observed. The rate of CR/CRi was further improved, to 60 percent, in the five treatment-naïve patients.
Response occurred rapidly in patients across all dose levels, the authors noted, with a mean time to full count recovery of five weeks for neutrophils (≥1,000/µL) and six weeks for platelets (≥100,000/µL).
“The rapid clearance of marrow blasts in patients with poor risk factors and low 30-day mortality are encouraging,” Dr. Stein and colleagues concluded. At the completion of dose-escalation, they recommended 40 mcg/kg SGN-CD33A as the optimal dose, providing the best response rates with manageable toxicity. Given these findings, researchers have initiated a trial investigating SGN-CD33A at 40 mcg/kg in patients with newly diagnosed CD33-positive AML, and multiple expansion cohorts are enrolling patients.
Stein AS, Walter RB, Erba HP, et al. A phase 1 trial of SGN-CD33A as monotherapy in patients with CD33-positive acute myeloid leukemia (AML). Abstract #324. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.