A Pilot Study of CX-01 with Azacitidine for Treatment of Hypomethylating Agent-Refractory AML and MDS

Hypomethylating agents are standard first line therapy for older patients with AML and MDS. While these agents can prolong overall survival and disease free survival, they are not curative and only result in a complete response in about 20-25% of patients. For patients that fail these agents, there are no standard treatment options and overall survival is short at 4-6 months.

Targeting the bone marrow microenvironment may be a valid strategy for treating refractory disease. CX-01, a 2-O, 3-O desulfated heparin, is a derivative of low molecular weight heparin with minimal anticoagulant activity, and may be potentially therapeutic as it blocks the CXCL12/CXCR4 axis and disrupts the HMGB1 interactions with TLR4 and RAGE, in addition to altering other vascular adhesion molecules.

We hypothesize that infusional CX-01 will disrupt the bone marrow microenvironment and increase the cytotoxic effects of azacitidine on MDS and AML hematopoietic stem cells. We designed a pilot study combining a continuous infusion of CX-01 0.25 mg/kg/hr x 7 days with azacitidine 75 mg/m2 daily x 7 days per 28 day cycle. 15 patients were enrolled with MDS INT-1 or higher and AML that were refractory to >4 cycles of prior hypomethylating agent therapy or progressed after a prior response. The primary objective was to assess the overall response rate. The study was approved by the institutional IRB.

To date, 13 patients have started treatment with the combination of infusional CX-01 and azacitidine. The median patient age is 73 years and 62% are male. Four patients have secondary AML, 4 have MDS INT-1, 2 have MDS INT-2, 2 have therapy related AML and 1 has de novo AML. Six patients have poor risk cytogenetics and pretreatment bone marrow biopsies revealed a median blast count of 16%. Patients were heavily pretreated, receiving a median of 6 cycles of prior hypomethylating agent therapy (range 4 - 20 cycles) with 7 patients receiving more than 1 prior line of therapy.

Three of the 13 patients have reached the first bone marrow assessment following cycle 2. Of these 3 evaluable patients, 2 patients have achieved a bone marrow CR. None of these patients yet have evidence of hematologic improvement per MDS IWG criteria. Treatment has been associated with 6 severe adverse events, including 3 cases of febrile neutropenia, an episode of recurrent fungal pneumonia, a case of cellulitis, and a case of grade 3 transaminitis. All AEs were thought unlikely to be related to therapy with CX-01. There have been several instances of prolonged PTTs causing dose delays or reductions but no cases of bleeding.

In conclusion, infusional CX-01 and azacitidine may be an effective treatment for hypomethylating agent-refractory AML and MDS. Based on this preliminary data it has a higher than expected rate of marrow CR, which was achieved in 2 of 3 evaluable patients. This treatment appears feasible with no instances of study-related severe adverse events. This trial is ongoing to evaluate the overall response rate and evaluate correlative data including blast mobilization and expression of CXCR4.