A Phase 2 Study of the Hedgehog Pathway Smoothened Inhibitor PF-04449913 to Reduce Relapse in High Risk Acute Leukemia and MDS Patients Following Allogeneic Stem Cell Transplantation

Relapse is the most common cause of allogeneic stem cell transplantation (SCT) failure. Non-cycling, chemoresistant leukemic stem cells (LSCs) are thought to contribute to disease relapse and have been shown to be dependent on signaling through the Hedgehog (Hh) pathway. Targeting this pathway represents a rational approach to the eliminate LSCs to prevent relapse. PF-04449913 (Pfizer) is a small molecule inhibitor of the transmembrane G protein-coupled Smoothened (SMO) receptor, a key mediator of the Hh pathway. PF-04449913 demonstrates single-agent activity in relapsed leukemias.

We designed an open label, Phase 2 study employing PF-04449913 in acute leukemia and MDS patients following SCT. Eligibility requirements include enrollment within 28-50 days of SCT, engraftment, and high risk of relapse. High relapse risk is defined for myeloablative conditioning regimens in acute leukemia as the presence of persistent morphologic disease or minimal residual disease (MRD) at the time of transplant as measured by flow cytometry, cytogenetics, or FISH, and, for MDS, persistent disease at the time of transplant with poor risk cytogenetics.  For non-myeloablative transplants, patients with a relapse risk score >0, as defined by the Fred Hutchinson Cancer Research Center scoring system, are also included.  Patients receive consecutive 28-day cycles of PF-04449913 at 100 mg/day for up to one year or until toxicity or relapse.  Twenty-eight patients are required for an 80% power to detect an estimated one year relapse free survival improvement from a null hypothesis of 30% to 53%.

To date 13 patients have enrolled including 9 AML, 3 ALL, and 1 MDS (7 myeloablative and 6 non-myeloablative). Median follow up is 176 days.   Three patients (one of whom relapsed) required dose reductions to 50 mg due to muscle cramps and dysgeusia, and one patient discontinued due to muscle cramps.  No other significant toxicities were attributed to the drug. Three patients relapsed including one morphologic, one MRD, and one with graft failure (developing prior to enrollment on study) with subsequent relapse. One patient died of GVHD, and 12 remain alive. One patient has completed the study and 7 remain on study with a median of 6 cycles completed (range 1-10). Preliminary data suggests that PF-04449913 is well tolerated early post-SCT and may reduce relapse rates.