Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

NCT02129101 | Completed Phase 1 DMC

• 4 other identifiers: MC1389NCI-2014-00866Mod13-009003-08P30CA015083
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Outcome Measures

Primary Outcomes (4)

• Best overall response (complete response [CR] or complete response with incomplete recovery [CRi]) in untreated AML, CMML, MDS, or MDS/MPN Overlap patients (Phase IB [Dose Expansion])

  The proportion of CR/CRi responses will be estimated (by cohort) by the number of CR/CRi responses divided by the total number of evaluable patients. 95% exact binomial confidence intervals will be computed. The frequency and relative frequency of individual response categories will also be computed. Best overall response over all cycles of study treatment will also be described using frequency and relative frequency of individual response categories.

  Up to 30 days post-treatment

• Best overall response (CR or CRi) in myelofibrosis patients (Phase IB [Dose Expansion])

  The proportion of CR/CRi responses will be estimated (by cohort) by the number of CR/CRi responses divided by the total number of evaluable patients. 95% exact binomial confidence intervals will be computed. The frequency and relative frequency of individual response categories will also be computed. Best overall response over all cycles of study treatment will also be described using frequency and relative frequency of individual response categories.

  Up to 30 days post-treatment

• Best overall response (CR or CRi) in relapsed/refractory AML, CMML, MDS, or MDS/MPN Overlap patients (Phase IB [Dose Expansion])

  The proportion of CR/CRi responses will be estimated (by cohort) by the number of CR/CRi responses divided by the total number of evaluable patients. 95% exact binomial confidence intervals will be computed. The frequency and relative frequency of individual response categories will also be computed. Best overall response over all cycles of study treatment will also be described using frequency and relative frequency of individual response categories.

  Up to 30 days post-treatment

• MTD defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)

  Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

  42 days

Secondary Outcomes (6)

• Duration of response

  Date at which the patient's earliest best objective status is first noted to be a CR/CRi response to the earliest date progression is documented, assessed up to 30 days post-treatment

• Incidence of adverse events graded using the NCI CTCAE version 4.0 (Phase IB [dose expansion])

  Up to 30 days post-treatment

• Overall survival

  Time from registration to death due to any cause, assessed up to 30 days post-treatment

• Time to AML

  Time from registration to leukemic transformation due to any cause, assessed up to 30 days post-treatment

• Time to death

  Time from registration to death due to any cause, assessed up to 30 days post-treatment

Other Outcomes (2)

• Biomarker levels

  Up to 30 days post-treatment

• Patient-reported outcomes (quality of life and symptoms) as assessed by the EORTC QLQ-C30 and MPN-SAF Total Symptom Score (TSS)

  Up to 30 days post-treatment

Study Arms (1)

Treatment (azacitidine, sonidegib, decitabine)

EXPERIMENTAL

Patients receive azacitidine SC or IV on days 1-7, sonidegib PO 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.

Drug: Azacitidine; Drug: Decitabine; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Sonidegib

Interventions

Azacitidine DRUG

Given SC or IV

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Treatment (azacitidine, sonidegib, decitabine)

Decitabine DRUG

Given IV

Also known as: 5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine

Treatment (azacitidine, sonidegib, decitabine)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (azacitidine, sonidegib, decitabine)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (azacitidine, sonidegib, decitabine)

Sonidegib DRUG

Given PO

Also known as: ERISMODEGIB, LDE-225, LDE225, Odomzo, Smoothened Antagonist LDE225

Treatment (azacitidine, sonidegib, decitabine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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)

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

Sponsors & Collaborators

• Mayo Clinic: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Links

• Mayo Clinic Clinical Trials

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic; Thrombocythemia, Essential; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Polycythemia Vera; Primary Myelofibrosis; Leukemia, Myeloid, Acute

Interventions

Azacitidine; Decitabine; Injections; sonidegib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Myeloproliferative Disorders; Hemorrhagic Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Aref Al-Kali

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2014
• First Posted: May 2, 2014
• Study Start: May 1, 2014
• Primary Completion: December 31, 2016
• Study Completion: October 25, 2019
• Last Updated: October 30, 2019

Record last verified: 2019-08

Locations

US (1)