P579: A PHASE 4 STUDY OF FRACTIONATED GEMTUZUMAB OZOGAMICIN ON QT INTERVAL AND SAFETY IN PATIENTS WITH RELAPSED/REFRACTORY CD33-POSITIVE ACUTE MYELOID LEUKEMIA

Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). Fractionated dosing of GO has demonstrated an enhanced safety profile without hampering efficacy. Aims: To assess the effect of fractionated GO as monotherapy on corrected QT (QTc) interval, safety, pharmacokinetics (PK), and immunogenicity of GO in patients (pts) with R/R AML. Methods: Pts aged ≥12 y with R/R AML were enrolled in a single-arm, open-label, phase 4 study (NCT03727750) and received a fractionated dose of GO 3 mg/m2 on days 1, 4, and 7 of each cycle, up to 2 cycles. Pts receiving ≥1 dose of GO were evaluable for QTc, safety, and PK. The primary endpoint was mean change from baseline in QTc. Secondary endpoints included PK parameters, adverse events (AEs), including veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), incidence of anti-drug antibodies (ADAs)/neutralizing antibodies (NAb), overall survival (OS), and response rate of complete remission (CR)/CR with incomplete hematologic recovery (CRi). This analysis includes data from pts aged ≥18 y. Results: Of 51 adult pts enrolled (median age 67 y), 50 (98%) pts received ≥1 dose of GO during cycle 1; 9 (18%) pts were treated with GO during cycle 2. The upper limit of the 2-sided 90% CI for least squares mean differences in QTc according to Fridericia’s formula (QTcF) was <10 msec for all timepoints during cycle 1 (Table). Most pts had a QTcF ≤450 msec (90%) and a maximum increase from baseline QTcF ≤30 msec (94%). No pts had a post-baseline QTcF >480 msec or a change from baseline >60 msec. Treatment-emergent AEs (TEAEs) occurred in 98% of pts; 54% were grade 3/4. The most common (>10%) grade 3/4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). One pt experienced grade 3 atrial fibrillation and supraventricular tachycardia, unrelated to GO. No pts experienced grade 4 or higher cardiac conduction TEAEs. VOD/SOS was not reported; however, one pt experienced treatment-related grade 5 capillary leak syndrome associated with pleural effusion, ascites, hyperbilirubinemia, and endothelial syndrome. The overall incidence of ADAs and NAbs were 12% and 2%, respectively. ADAs were persistent in 5/6 pts (83%). Of the 6 pts with treatment-induced ADAs, 2 experienced pyrexia (grade 1 and grade 3) within 24 h of the infusion. Among ADA-negative pts (n=44), infusion-related reactions were observed in 7 (16%) pts. These were grade 1/2, except for 1 instance of grade 3 urticaria. Median (95% CI) OS was 2.8 (1.7–4.2) mo. Disease progression was the most common cause of death in 35/45 (78%) pts. A CR/CRi was observed in 5/51 (10%) pts. Image:Summary/Conclusion: Fractionated dosing of GO (3 mg/m2 per cycle) is not predicted to pose a clinically significant safety risk for QT prolongation in pts with R/R AML, with the upper limit of the 2-sided 90% CI for the least squares mean change from baseline falling below the 20 msec threshold of clinical concern for oncology drugs. TEAEs reported in this study are consistent with the known safety profile of GO, and the presence of ADAs does not appear to be associated with any potential safety concerns. Response rates were lower than previously reported in the MyloFrance 1 study, which included less heavily pretreated patients (i.e., patients only in first relapse; Taksin et al, Leukemia, 2007).