CD33 is a sialoglycan protein expressed on normal myeloid and monocytic cells as well as the vast majority of myeloid malignancies. A humanized antibody (HuM195) has been developed that specifically recognizes CD33 and induces potent effector function (ADCC, CDC, ADCP). In prior clinical testing, this antibody led to antitumor activity and objective responses in patients with relapsed and refractory AML. To further characterize a dose-response relationship and because a maximum tolerated dose for SGN-33 has never been identified, a phase I single-arm dose escalation trial was initiated at multiple sites to assess safety, immunogenicity, PK, and activity of SGN-33 at substantially increased dose intensity and in a patient (pt) population not previously tested, including untreated AML and MDS. Entry criteria included CD33 expression on >50% of the marrow blasts to ensure that adequate target antigen was present. Cohorts of 3–6 pts with advanced myeloid malignancies were planned to receive IV SGN-33 at weekly doses of 1.5 to 8 mg/kg for 5 weeks. Response was assessed by marrow morphology and hematologic improvement. Pts demonstrating clinical benefit were eligible for additional infusions. To date, 12 pts have been treated at a maximum weekly dose of 1.5 mg/kg (N=6), 2.5 mg/kg (N=4), or 4 mg/kg (N=2). The median age was 74.5 years (range 52–88), and the majority of pts were previously untreated. Eight pts had a diagnosis of AML and four had MDS. SGN-33 has been well tolerated; drug-related AEs so far include mild to moderate infusion reactions (Day 1 only) and mild rash. One pt experienced tumor lysis syndrome after the first week of treatment; laboratory abnormalities returned to baseline after hydration. There has been no dose-limiting toxicity or related adverse events > grade 3. No anti-SGN-33 immune responses were detected among the first 8 pts tested. CD33 saturation of the marrow blasts after two infusions for Cohorts I and II averaged 55.4% and 89.0%, respectively. Three pts did not complete 1 cycle (ie five weeks) of treatment due to: disease progression (1), thrombocytopenia refractory to transfusion (1), and pt withdrawal after a Grade 2 infusion reaction (1). Six of the seven pts that completed Cycle 1 received additional infusions after demonstrating one or more of the following: improved blood counts, decreased transfusion requirements, or decreased blasts. There was no unresolved toxicity after the first cycle of therapy and no evidence of cumulative toxicity during Cycle 2. Two pts demonstrated a marked decrease in the percentage of blasts in the marrow at the end of Cycle 1 compared to baseline. In summary, SGN-33 has been well tolerated at a dose intensity substantially higher than previously achieved, and antitumor activity was observed in elderly pts with untreated AML and MDS. SGN-33 holds promise as single-agent therapy and/or in combination with other non-myeloablative therapies for the treatment of pts with myeloid malignancy who are ineligible for aggressive therapy.

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