Clinical Trials /

Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

NCT02129101

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Promyelocytic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies
  • Official Title: Phase I/Ib Study of Azacitidine or Decitabine With Hedgehog Pathway Inhibition in Myeloid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: MC1389
  • SECONDARY ID: NCI-2014-00866
  • SECONDARY ID: Mod13-009003-08
  • SECONDARY ID: MC1389
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02129101

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

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, sonidegib, decitabine)
Decitabine5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (azacitidine, sonidegib, decitabine)
SonidegibERISMODEGIB, LDE-225, LDE225, Odomzo, Smoothened Antagonist LDE225Treatment (azacitidine, sonidegib, decitabine)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, sonidegib, decitabine)ExperimentalPatients 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.
  • Azacitidine
  • Decitabine
  • Sonidegib

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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])
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Duration of response
Time Frame: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
Safety Issue:
Description:The distribution of duration of response will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events graded using the NCI CTCAE version 4.0 (Phase IB [dose expansion])
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (by cohort and overall). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with a 95% exact binomial confidence interval.
Measure:Overall survival
Time Frame:Time from registration to death due to any cause, assessed up to 30 days post-treatment
Safety Issue:
Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.
Measure:Time to AML
Time Frame:Time from registration to leukemic transformation due to any cause, assessed up to 30 days post-treatment
Safety Issue:
Description:The distribution of time to AML will be estimated using the method of Kaplan-Meier.
Measure:Time to death
Time Frame:Time from registration to death due to any cause, assessed up to 30 days post-treatment
Safety Issue:
Description:The distribution of time to death will be estimated using the method of Kaplan-Meier.
Measure:Time to progression
Time Frame:Time from registration to the earliest date of documentation of disease progression, assessed up to 30 days post-treatment
Safety Issue:
Description:The distribution of time to progression will be estimated using the method of Kaplan-Meier.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Mayo Clinic

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