This phase II trial will test whether the Hedgehog signaling pathway inhibitor PF-04449913 can decrease disease relapse in high-risk patients with acute myeloid leukemia after donor stem cell transplant.

Disease relapse is the most common cause of death after allogeneic stem cell transplantation for acute myeloid leukemia. Patients at high risk for relapse may benefit from a novel, biologically rational therapeutic intervention to prevent this outcome. PF-04449913 is a small molecule inhibitor of the hedgehog (Hh) pathway that inhibits the protein Smoothened (SMO). Aberrant Hh signaling may contribute to the survival and expansion of the leukemia stem cell, and inhibiting the Hh pathway can eliminate these cells. Therefore, targeting Hh may be a logical intervention in the post-transplantation setting for those with high risk of relapse. The investigators propose a phase 2 study of PF-04449913 in patients with acute myeloid leukemia who have received an allogeneic stem cell transplantation and are at high risk of relapse.

This is an open label, phase 2 study employing PF-04449913 in acute myeloid leukemia patients who received an allogeneic stem cell transplantation and are at high risk of relapse. Patients will receive consecutive 28-day cycles of PF-04449913 at 100 mg/day, beginning on post-transplantation day 80 +/- 10 days, after their routine post-transplant bone marrow biopsy. Treatment will continue for up to one year or until they experience toxicity or disease relapse. 50 patients will be required for a 90% power to detect a 20% difference in one-year relapse-free survival.

Inclusion Criteria:

• WHO-confirmed AML

• Age ≥18 years

• Between days 28 and 50 post transplantation at the time of initiation of the study drug

• ECOG performance status ≤ 2 (See Appendix A: ECOG Performance Status Scale)

• Life expectancy > 2 months

• Recipient of a myeloablative or non-myeloablative allogeneic HSCT

  • Conditioning regimen to be prescribed at investigator's discretion, but will be prospectively defined as myeloablative or non-myeloablative

• Stable engraftment, as defined by absolute neutrophil count (ANC) ≥ 1000/mm3 and platelets ≥ 25,000/mm3

• In morphologic remission (< 5% marrow blasts) based on BM biopsy performed +/- 5 days of day 28 post- transplantation

• Without clinical signs of active central nervous system disease

• For non-myeloablative transplants, ≥50% CD3 donor chimerism at screening

• High risk of relapse after HSCT, defined as the presence of minimal residual disease as measured by flow cytometry in the absence of evidence of morphologic disease on a bone marrow biopsy prior to HSCT

• Adequate organ function as indicated by the following laboratory values:

  • Aspartate aminotransferase (AST), alanine aminotransferase, (ALT) ≤ 3.0 x institutional upper limit of normal (ULN)
  • Total bilirubin ≤ 2.0 x institutional ULN, unless documented Gilbert's syndrome
  • Either creatinine <1.5 x institutional upper limit of normal (ULN) or creatinine clearance >60 mL/min as calculated by institution's standard formula

• Serum/urine pregnancy test (for females of childbearing potential) that is negative within 72 hours prior to initiation of first dose of treatment (a patient is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active)

• Female patients of childbearing potential and sexually active males and female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 90 days after the last dose of assigned treatment.

• Subject is able to comply with study procedures and follow-up examinations.

Exclusion Criteria:

• Concomitant treatment with other anti-neoplastic agents, with the exception, when clinically indicated, of prophylaxis in the post-transplantation setting with intrathecal chemotherapy
• Use of any other experimental drug or therapy within 28 days of baseline
• Inability to swallow or absorb drug
• Active uncontrolled acute fungal, bacterial, or other infection that is unresponsive to therapy at time of study drug dosing
• Unstable angina pectoris
• New York Heart Association Class III or IV heart failure
• QTc interval (using Fridericia's correction formula, QTcF, if prolonged) >470 msec
• Active cardiac arrhythmias with rapid ventricular response (defined as heart rate greater than 100 beats/minute)
• Known HIV infection
• Grade III/IV acute GVHD
• Current use or anticipated need for food or drugs that are known moderate/strong CYP3A4 inducers (See Table 1 and section 5.9.2: Prohibited Concomitant Therapy), with the exception of azole antifungals, which are permitted.
• Any medical, psychiatric, addictive or other kind of disorder which compromises the ability of the subject to give written informed consent and/or to comply with procedures.
• Pregnant or lactating females