Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

Myelodysplastic Syndrome Clinical Trial

Official title: Phase I/Ib Study of Azacitidine or Decitabine With Hedgehog Pathway Inhibition in Myeloid Malignancies

Status Completed

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Chronic Myelomonocytic Leukemia
• de Novo Myelodysplastic Syndrome
• Essential Thrombocythemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm
• Myeloproliferative Disorders
• Polycythemia
• Polycythemia Vera
• Preleukemia
• Previously Treated Myelodysplastic Syndrome
• Primary Myelofibrosis
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Syndrome
• Thrombocythemia, Essential
• Thrombocytosis
• Untreated Adult Acute Myeloid Leukemia

• NCT number: NCT02129101
• Study type: Interventional
• Source: Mayo Clinic
• Status: Completed
• Phase: Phase 1
• Start date: May 2014
• Completion date: October 25, 2019