Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

PRIMARY OBJECTIVES:

I. To estimate the maximally tolerated dose (MTD) of LDE225 (sonidegib) (days 1-28) in
combination with azacitidine (overall); LDE225 (days 1-7) in combination with azacitidine
(overall); and LDE225 (days 1-28) in combination with decitabine (overall). (Phase I) II. To
estimate the efficacy of LDE225 (days 1-28) in combination with azacitidine in the following
subgroups: untreated acute myeloid leukemia (AML)/chronic myelomonocytic leukemia
(CMML)/myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap;
relapsed/refractory AML/CMML/MDS/MPN overlap; and myelofibrosis (MF) only. (Phase Ib)

SECONDARY OBJECTIVES:

I. To estimate the duration of response, time to progression, overall survival, and time to
AML or death (for MDS subjects) of LDE225 (days 1-28) in combination with azacitidine
(overall and by cohort). (Phase I/1b)

TERTIARY OBJECTIVES:

I. To conduct correlative studies to measure HH pathway activation and inhibition and explore
biomarkers of response.

II. To evaluate quality of life (QOL) and patient-reported symptoms using the
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and European Organization for
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30 in
subjects treated with LDE225 in combination with azacitidine or decitabine.

OUTLINE: This is a dose-escalation study of erismodegib.

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7, sonidegib
orally (PO) once daily (QD) on days 1-28 or 1-7* or decitabine IV on days 1-5. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

*NOTE: Sonidegib PO QD is given on days 1-7 if in combination with azacitidine or on days
1-28 is given if in combination with decitabine.

After completion of study treatment, patients are followed up every 3 months until
progressive disease and then every 6 months for 2 years.

Inclusion Criteria:

- Patients with one of the following diagnoses:

- Intermediate, high and very high risk (per International Prognostic Scoring
System [IPSS]-revised [R]) untreated MDS or any MDS with >= 5% marrow blasts (by
French American British [FAB] and World Health Organization [WHO] diagnostic
criteria); NOTE: MDS/MPN overlap is allowed

- CMML requiring treatment per doctor of medicine (MD) judgment

- Low and very low risk MDS patients symptomatic and/or transfusion dependent, (>=
4 U red blood cells [RBC] over the preceding 12 week period) who have failed
erythropoietin-stimulating agents (ESAs) or who have a low likelihood of
responding to ESAs

- MDS and CMML patients relapsed/refractory to hypomethylating agents as evidenced
by one of the following:

- Progressed at any time during treatment with hypomethylating agents

- Failed to achieve a response after 6 cycles of 5-azacytidine or 4 cycles of
decitabine

- Progressed after treatment with hypomethylating agents had been discontinued

- NOTE: MDS/MPN overlap is allowed

- Relapsed or refractory AML exposed to =< 3 prior regimens (note, induction and
consolidation including stem cell transplantation count as one regimen)

- For exploratory phase I LDE225 days 1-7 with azacitidine or LDE225 days 1-28 with
decitabine cohorts only: untreated AML/CMML/MDS/MPN overlap or
relapsed/refractory AML/CMML/MDS/MPN overlap WITHOUT prior exposure to a
hypomethylating agent (HMA)

- Elderly (age >= 60) untreated AML and not a candidate for induction therapy

- Untreated AML < 60 year of age who are not candidates to undergo standard
induction chemotherapy

- Primary myelofibrosis (PMF) and post essential thrombocytopenia (ET)/polycythemia
vera (PV) MF with a Dynamic International Prognostic Scoring System (DIPSS)-plus
score of intermediate or high, or a > 10% blasts in the marrow and who are in
need of therapy and who have failed previous treatment with a janus kinase 2
(JAK2) inhibitor and, if appropriate, have failed Interferon based treatment

- Total bilirubin =< 1.5 mg/dL (except Gilbert's syndrome or known hemolysis or leukemic
infiltration)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
upper limit of normal (ULN) or < 5 x ULN if organ involvement

- Alkaline phosphatase < 5 x ULN

- Serum creatinine =< 1.5 x ULN or 24 hour creatinine (Cr) clearance > 50 ml/min

- Plasma creatine phosphokinase (CK) < 1.5 x ULN

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

- Ability to provide informed written consent and be able to adhere to the study visit
schedule and other protocol requirements

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Willing to provide blood and bone marrow aspirate samples for correlative research
purposes

- Negative serum pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Men must be willing to use appropriate contraception throughout study and for 6 months
after; women must be willing to use appropriate contraception throughout study and for
20 months after

- Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic,
are eligible provided that they are > 84 days from stem cell infusion, have no active
graft-versus-host disease (GVHD), are off immunosuppressive agents for > 14 days

- In the opinion of the investigator, patient must be able to receive at least 2 cycles
of treatment

Exclusion Criteria:

- Uncontrolled intercurrent illness including, but not limited to, active uncontrolled
infection, known positive for active infectious hepatitis, type A, B or C; (past
infection allowed), or psychiatric illness/social situations that would limit
compliance with study requirements; Note: ongoing infection controlled on
antibiotics/antifungal/antiviral medications are allowed unless listed as
contraindicated

- Any of the following prior therapies:

- Cytotoxic chemotherapy =< 14 days prior to registration

- Immunotherapy =< 14 days prior to registration

- Biologic therapy (i.e. antibody therapies) =< 14 days prior to registration

- Radiation therapy =< 14 days prior to registration

- Targeted therapies (i.e. kinase inhibitors, =< 7 days or 5 half-life's whichever
is shorter)

- Patients must be off other biologic therapies including hematopoietic growth
factors >= 7 days prior to registration

- For steroids or other non-cytotoxics given for blast count control, patient must
be off for > 24 hours (hrs) before starting therapy; NOTE: hydroxyurea (HU) is
allowed for blast count control throughout study

- Receiving any other investigational agent which would be considered as a
treatment for the primary neoplasm =< 14 days prior to registration

- Active uncontrolled central nervous system (CNS) leukemia; NOTE: positive
(cyto)pathology is allowed and patient can receive intrathecal chemotherapy

- Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
positive and currently receiving antiretroviral therapy; NOTE: patients known to be
HIV positive, but without clinical evidence of an immunocompromised state, are
eligible for this trial

- Any previous treatment with LDE225 or allergic reactions to excipients of LDE225

- Acute promyelocytic leukemia (APL, M3) unless failed regimens that included tretinoin,
arsenic trioxide, anthracyclines and cytarabine and currently NOT candidates for stem
cell transplantation

- Major surgery =< 28 days prior to registration

- Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular
dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on
concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as
3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors (statins), clofibrate and
gemfibrozil, and that cannot be discontinued at least 5 half lives prior to starting
LDE225 treatment; NOTE: if it is essential that the patient stays on a statin to
control hyperlipidemia, only pravastatin may be used with extra caution

- Patients who are planning on embarking on a new strenuous exercise regimen after
initiation of study treatment; NOTE: muscular activities, such as strenuous exercise,
that can result in significant increases in plasma creatine kinase (CK) levels should
be avoided whilst on LDE225 treatment

- Patients who are receiving treatment with medications known to be moderate and strong
inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4
(CYP3A4)/cytochrome P450, family 3, subfamily A, polypeptide 5 (5) or drugs
metabolized by cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6) or
cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) that have narrow
therapeutic index, and that cannot be discontinued before starting treatment with
LDE225; medications that are strong CYP3A4/5 inhibitors should be discontinued at
least 7 days and strong CYP3A4/5 inducers for at least 2 weeks prior to starting
treatment with LDE225; NOTE: patients who are already on or require initiation of
azoles other than fluconazole will be excluded from the phase I dose escalation
portion of the study

- Impaired cardiac function or clinically significant heart disease, including any one
of the following:

- Angina pectoris within 3 months

- Acute myocardial infarction within 3 months

- Corrected Fridericia's QT (QTcF) > 450 msec for males and > 470 msec for females
on the screening electrocardiogram (ECG)

- A past medical history of clinically significant ECG abnormalities or a family
history of prolonged QT-interval syndrome

- New York Heart Association classification IV cardiovascular disease or
symptomatic class III disease

- Other clinically significant heart disease (e.g. congestive heart failure,
uncontrolled hypertension, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen)

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception during the study and through 20 months after the final dose of
study treatment if female, and for 6 months after final dose of study treatment
if male

- NOTE: adequate contraception is defined as either:

- Total abstinence: when this is in line with the preferred and usual
lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception

- Sterilization: patient has had surgical bilateral oophorectomy (with or
without hysterectomy) or tubal ligation at least six weeks before taking
study treatment; in case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

- Male partner sterilization (with the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate); (for female study
patients, the vasectomized male partner should be the sole partner for that
patient)

- Use a combination of the following:

- Placement of a non-hormonal intrauterine device (IUD) or non-hormonal
intrauterine system (IUS)

- Barrier method of contraception: condom or occlusive cap (diaphragm or
cervical vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository

- Note: hormonal contraception methods (e.g. oral, injected,
implanted) are not allowed as it cannot be ruled out that the
study drug decreases the effectiveness of hormonal contraception

- Note: women are considered post-menopausal and not child bearing
potential if they have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or six months of
spontaneous amenorrhea with serum follicle stimulating hormone
(FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL or have had
surgical bilateral oophorectomy (with or without hysterectomy) at
least six weeks ago; in the case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow
up hormone level assessment is she considered not of child bearing
potential

- Note: male patient must use highly effective (double barrier)
methods of contraception (e.g., spermicidal gel plus condom) for
the entire duration of the study, and continuing using
contraception and refrain from fathering a child for 6 months
following the study drug; a condom is required to be used also by
vasectomized men as well as during intercourse with a male partner
in order to prevent delivery of the study treatment via seminal
fluid