Phase I Trial of Nanomolecular Liposomal Annamycin in Adult Patients with Refractory Acute Lymphoblastic Leukemia.

Abstract 4098

There continues to be no effective second line therapy for refractory acute lymphoblastic leukemia (ALL) in adult patients and the cure rate with current therapy has not significantly improved in decades. Annamycin is a highly lipophilic form of the anthracycline doxorubicin with the ability to bypass multi-drug resistance (MDR-1) mechanisms of cellular drug resistance. A novel nanomolecular liposomal entity of annamycin was recently specifically synthesized which overcomes MDR with little to no cardiac toxicity and improved anti-tumor activity when compared to the original annamycin formulation. We performed a phase I multi-center, open-label, study to determine the maximally tolerated dose (MTD) of nanomolecular liposomal annamycin in adult patients with refractory ALL. The secondary objective was to study the MDR-1 encoded (permeability glycoprotein) PgP-170 glycoprotein expression in correlation with CD34 expression and MDR-1 mRNA levels in refractory ALL patients prior to and after receiving liposomal annamycin treatment. Thirty patients were enrolled on the study. The MTD was determined to be 150 mg/m²/day for 3 days. Other than the tumor lysis syndrome, there was only 1 severe adverse event (SAE) definitely related to the study drug consisting of grade 3 mucositis. There were also 3 other SAEs of grade 3-4 mucositis probably related to the study drug which comprised the MTD determination. There was no reported cardiac toxicity in any patients. After determining the MTD, a 10-patient phase IIA was conducted. Eight of the patients completed 1 cycle of the 3 days of treatment at the MTD. Of these, 5 (62%) had an efficacy signal with complete clearing of circulating peripheral blasts. Three of these subjects also cleared bone marrow blasts with one subsequently proceeding onto successful stem cell transplantation. The other 2 developed tumor lysis syndrome and unfortunately expired prior to response assessment. Nanomolecular liposomal annamycin appears to be well-tolerated with no cardiotoxicity and evidence of clinical activity as a single agent in refractory adult ALL. Given that the likely mechanism of action is overcoming innate drug resistance via MDR, PgP-170 mRNA and protein expression will be presented. We are currently testing liposomal annamycin in a phase I study in children and young adults with refractory ALL or AML, and planning a phase 2 registration trial in adult ALL