Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

Completed · Phase 1

Conditions studied: Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Essential Thrombocythemia, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Polycythemia Vera, Previously Treated Myelodysplastic Syndrome, Primary Myelofibrosis, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

In brief

This phase I/Ib trial studies the side effects and best dose of azacitidine and sonidegib or decitabine and so see how well they work in treating patients with myeloid malignancies. The hedgehog (Hh) signaling pathway plays an important role in cellular growth, differentiation and repair. Inappropriate activation of Hh pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hh-ligand cell surface receptor Smo. Sonidegib binds to the Hh cell surface receptor Smo, which may result in the suppression of the Hh signaling pathway and the inhibition of cancer cells. Azacitidine and decitabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with sonidegib or decitabine may be a safe and successful treatment for patients with myeloid malignancies.

Key facts

Study ID: NCT02129101
Run by: Mayo Clinic
People needed: 63
Starts: 2014-05-01
Expected to finish: 2019-10-25
Last updated by the study team: 2019-10-30

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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

You may not qualify if…

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)

Where it is running

Mayo Clinic — Rochester, Minnesota, United States

Full record on ClinicalTrials.gov

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