A Phase II multi-center, open label, randomized study to assess safety and efficacy of two different schedules of oral LDE225 in adult patients with relapsed/refractory or untreated elderly patients with acute leukemia

There has been no significant change in the standard management of acute
myeloid leukemia (AML) in the last 20 years. Only ~45% of AML
patients younger than 60 years are alive after 5 years compared with <10% of
older patients. Adult acute lymphoblastic leukemia (ALL) has a
much poorer prognosis than its childhood counterpart, with long term overall
survival of 35% in patients 18 to 60 years, and less than 10% in elderly
patients. Thus, relapsed and refractory adult acute leukemia still remains an
area of high unmet medical need.

During the last several years, substantial progress has been made regarding the
biologic characterization of the acute leukemias. The traditional understanding
that myeloid leukemic cells are developmentally similar to their normal
hematopoietic counterparts, and that the disease may be driven by a small
subset of stem cells, has been established via extensive studies using both
primary human tissues and various mouse models. Studies have clearly
demonstrated that AML populations are highly heterogeneous and that the disease
is propagated by a subpopulation of leukemic stem cells (LSC). Similar evidence
has been published for ALL. Cells with LSC properties have low sensitivity to
chemotherapy, and might contribute to treatment failure and disease relapse,
providing a clear rationale for targeting the possible mechanisms involved in
LSC maintenance and self-renewal.
It has been recently demonstrated that Hh signaling has a role in the
selfrenewing of ALL cells, as shown by treating ALL cell lines with Smo
inhibitors, and demonstrating decreased in vitro colony-formation and serial
transplantation in mice, reflecting effects on the self-renewing population.
Also, Hh signaling has been reported to be active in human AML cells,
especially primary CD34+ leukemic cells and aberrant up-regulation of the
pathway has been implicated in the development, self-renewal, and survival of
LSC.
Preliminary clinical activity has been reported in a phase I dose-escalation
study of an oral Hh inhibitor as single agent in 6 out of 18 patients with
AML. These data suggest that Hh inhibition may have the potential to induce
responses in heavily pretreated and poor prognostic AML patients. All of the
aforementioned findings provide the rationale for testing the efficacy of
LDE225, a potent inhibitor of the Hh pathway, in relapsed/refractory acute
leukemia.

This is a multi-center, open label, randomized, phase II study. The study will
evaluate the efficacy, safety and pharmacokinetics of two LDE225
dosing schedules in patients with relapsed/refractory acute leukemia or elderly
patients with untreated acute leukemia. Approximately 80 patients, consisting
of adults with relapsed/refractory AML or ALL and elderly patients with
untreated AML or ALL (if deemed to be unsuitable for standard chemotherapy)
will be enrolled in this study. After signing the Informed Consent Form (ICF)
and completing screening assessments, patients will be randomized to either 400
mg BID or 800 mg QD dose schedule in a 1:1 fashion in two stages (1 and 2). The
patients
randomized to 400 mg BID schedule arm will receive 400 mg BID for the first 2
weeks and continue with 800 mg QD thereafter.
Schedule A: LDE225 400mg BID for 2 weeks, then 800 mg QD
Schedule B: LDE225 800 mg QD
Patients will be assessed for efficacy (peripheral blood blast count) at
screening (before initiation of study treatment) and every week up to week 9
and every 2 weeks thereafter until complete remission (CR or CRi) and then
every 4 weeks after complete remission (CR or CRi). Efficacy will also be
assessed by bone marrow assessments as described below (refer to visit Table
7-1 for details). Visit assessments can be done in ±1 day and bone marrow
assessments in ±3 days of the scheduled visit.
Overall Response Rate (ORR) i.e., the proportion of patients who achieve CR,
CRi or PR, will be assessed according to the International Working
Group (IWG) criteria for response assessment in AML patients as outlined in
Appendix 2. The same response categories will be used for assessing response in
AML and ALL patients, according to standard clinical practice.
Overall survival (OS) will be assessed for the two different dosing schedules.
An interim futility analysis (IA) will be performed after 40 patients are
randomized (i.e. 20 patients/schedule) in Stage 1 and followed for a minimum 8
weeks or discontinued treatment due to death, disease progression, withdrawal
of consent or lost-to-follow-up. In this exploratory study, efficacy signal is
defined as the observation of CR/CRi in at least 2 patients (out of 20) in
either schedule during Stage I. Further enrollment on either schedule will be
stopped after the futility analysis if there are less than 2 patients with
CR/CRi in that schedule. Patient enrollment will not be suspended while data
for the interim analysis is being collected and assessed.
The primary analysis of study data will be performed after the last enrolled
patient has been treated for 16 weeks or discontinued treatment due to death,
disease progression, withdrawal of consent or lost-to-follow-up. A final
analysis of the core study will be performed after the last enrolled patient
has been followed for up to 53 weeks or discontinued treatment due to death,
disease progression, withdrawal of consent or lost-to-follow-up. However,
patients who are benefitting from the study treatment will continue to receive
LDE225 on a separate protocol.

Not Applicable.

Risk:
Side effects of the study medication, drawing blood samples and tissue
biopsies. Het collection of blood can cause a bruise, bleeding at the site or
blood clothing. These usually disappear naturally.

Burden:
-study visits first every week (for 9 weeks) and then varying every 2 or 4
weeks depending on the achievement of complete remission (CR or CRI) or the
Post Treatment or Survival Follow-Up.
-blood draws for lab tests every visit
-other assessments such as tissue biopsies, ECGs and possible radiology tests