PF-04449913 For Patients With Acute Myeloid Leukemia at High Risk of Relapse 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