Trial-in-Progress: A Phase 2 Study of Mitoxantrone, Etoposide and Gemtuzumab Ozogamicin (MEGO) for Acute Myeloid Leukemia That Persisted after the 1^st Induction Regimen

Background Acute myeloid leukemia (AML) is a disease characterized by a clonal proliferation of myeloid precursors with reduced capacity to differentiate into more mature cellular elements. The standard treatment for newly diagnosed AML has not changed appreciably over the last few decades and consists primarily of an anthracycline combined with a nucleoside analogue. Complete remission (CR) rates of 65-80% can be expected in younger patients but decrease with older age. There is no agreed standard of care for AML patients that do not respond to initial first line induction therapy. Although remission after second-line therapy may occur, the CR rate is lower. A few chemotherapy regimens have been used in patients with resistant disease with overall CR rates of 20-40%.

Gemtuzumab ozogamicin (GO) is an antibody drug conjugate consisting of a recombinant humanized antibody to CD33 which is linked to calicheamicin. Although GO is currently approved for induction therapy in combination with "7+3", its benefit is mostly evident in favorable risk disease (Hills et al Lancet Onc 2014) and thus its use is mostly limited in this setting. Pre-clinical data suggest that GO is most effective when it saturates CD33 which happens in low-burden disease (Van der Velden et al Leukemia 2004). Thus, we decided to proceed with a trial that incorporates gemtuzumab ozogamicin on the 2^nd induction regimen for patients that did not achieve complete remission with the first.

Methods This is a phase II, singe-center clinical trial of GO in combination with mitoxantrone and etoposide in patients with AML that persisted after their 1^st induction regimen. The patients are eligible if they have at least 10% of blasts in their day 14 bone marrow biopsy and CD33 expression in at least 30% of leukemic blasts in the bone marrow. Patients with repeat bone marrows after day 14 showing progression of AML (>5% blasts) were also eligible. Patients also need to have ECOG performance status 0-2, left ventricular ejection fraction (LVEF) >50%, GFR > 30 ml/min, AST/ALT < 2.5 x upper normal limits and total bilirubin <2 x upper normal limit. Patients that received CPX-531 for induction are excluded due to concerns for prolonged thrombocytopenia. The standard of care for our center for this patient population is 10mg/m2 of mitoxantrone on days 1-5 and 100mg/m2 of etoposide on days 1-5. Trial patients receive the same regimen and a single dose of GO 3mg/m2 (capped at 4.5mg) on day 6. The primary endpoint of the trial is complete remission rate (CR). The hypothesis is that addition of GO to mitoxantrone, and etoposide will increase our historical CR rate of 35% to 50%. The trial has a Simon's two-stage design, with an interim analysis planned after 16 evaluable patients have been enrolled. The trial plans to accrue 44 evaluable patients. This design has an alpha of 0.15 and 80% power. Secondary objectives include progression-free survival, overall survival, and treatment-related mortality. To-date we have enrolled 15 patients, 13 of them evaluable. 2 patients died from sepsis before the administration of GO. We have not recorded any episodes of VOD so far. Recruitment is continuing and this trial is registered on clinicaltrials.gov; NCT03839446.

Redner:Pfizer: Current equity holder in publicly-traded company. Agha:GenCART Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Im:CTI Biopharma: Consultancy; Abbvie: Consultancy; Incyte: Research Funding. Dorritie:Kite, BMS, Janssen, Genmab, Hoffman-LaRoche: Research Funding. Sehgal:Juno: Other: Grants, Research Funding; Milltenyiz: Research Funding; Kite, a Gilead Compnay: Other: Grants, Research Funding; PeerView: Honoraria; OncLive: Honoraria. Boyiadzis:Genentech: Current Employment.