FDA Grants Fast-Track Designation to CX-01 for Acute Myeloid Leukemia

The US Food and Drug Administration has granted fast-track designation to Cantex’s CX-01, which is used to treat patients aged 60 and older who are receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).

Fast-track designation is intended to expedite the development and review of drugs that fill an unmet clinical need. According to Peter Westervelt, MD, PhD, professor of medicine at Washington University School of Medicine and an expert in the treatment of AML and myelodysplastic syndrome (MDS), the need for CX-01 is great.

“Despite the recent advent of novel molecularly targeted therapies, older adults with AML and advanced MDS are rarely cured with available chemotherapeutic agents, outside of allogeneic stem cell transplantation, and development of better treatment options for these diseases remains a significant unmet need,” Westervelt told Cancer Network.

Mechanism of CX-01

CX-01 is a low-anticoagulant heparin derivative that has been studied in the treatment of newly diagnosed AML as well as refractory MDS. In AML, relapses are common because quiescent leukemic stem cells (LSCs) abscond to marrow stromal niches. In these niches, LSCs resist chemotherapy.

Hematopoietic stem cells migrate to and are anchored by chemotactic signals that the bone marrow stroma produces. In the bone marrow, HSCs alternatively induce quiescence or promote proliferation and differentiation.

Quiescence in the endosteal niche is facilitated by megakaryoctes. Megakaryocytes negatively regulate HSC proliferation via the secretion of the chemokine platelet factor-4 (PF4). CX-01 binds PF4 with an affinity akin to heparin; however, the CX-01/PF4 complex does not bind antibodies that mediate heparin-induced thrombocytopenia.

In addition to blocking PF4, which hampers bone marrow recovery after chemotherapy, CX-01 also blocks chemokines CXCR4 and CXCL12, which are necessary for blood cancer cells to attach to the protective bone marrow environment.

 “CX-01 appears to disrupt the leukemic stem cell niche by disrupting cytokine and signaling pathways within the leukemic niche that are protective of leukemic stem cells. It is hypothesized that CX-01 may enhance the sensitivity of leukemic cells to chemotherapy, Catherine M. Diefenbach, MD, an assistant professor of medicine at the Perlmutter Cancer Center at NYU School of Medicine and a participant in the American Society of Clinical Oncology’s Leadership Development Program, told Cancer Network. “Additionally it may neutralize platelet factor-4, a chemokine which inhibits bone marrow recovery after chemotherapy,” she said.

CX-01 Pilot Study

In a pilot study published in Blood Advances, researchers combined CX-01 with chemotherapy to treat AML. Cytarabine and idarubicin (i.e., 7+3) served as induction, in addition to CX-01. A total of 12 patients (median age 56 years; 3 women) were enrolled, with 3 patients exhibiting good-risk disease, 5 exhibiting intermediate-risk disease, and 4 exhibiting poor-risk disease.

At Day 14, bone marrow specimens from 11 patients were aplastic in those without detectable leukemia.  Overall, 11 of 12 patients (92%) exhibited morphologic complete remission after one induction, with 3 patients receiving an allogenic stem cell transplant at this point. Furthermore, 8 of 12 patients lived at a median follow-up of 24 months, with 4 in complete remission after one induction.

The median disease-free survival was 14.8 months, and median overall survival was not reached at 29.4 months of follow-up. In addition to demonstrating good rates of complete remission, this preliminary study also demonstrated rapid rates of platelet recovery, as well as no serious adverse events related to CX-01.

Future Implications

Diefenbach reflected on the significance of the Kovacsovics et al trial and what it means for CX-01. “CX-01 was associated with an encouraging complete response rate of 92% compared to the historical control of 71%,” she said. “Patients also appeared to have a more rapid hematologic recovery rate without the use of growth factors. However, these findings will need to be confirmed in larger numbers of patients.”

Dr. Westervelt and other experts recognize the promise that CX-01 holds. “It is hoped that CX-01 will be shown to enhance response rates, prolong survival, and provide a better bridge to transplant for selected patients when used in combination with existing therapeutic options,” Westervelt told Cancer Network.