AzTrials
AzTrials

Chronic Myelomonocytic LeukemiaPhase 1NCT02129101

Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies

A Phase 1 study testing Azacitidine, Decitabine and Laboratory Biomarker Analysis in people with Chronic Myelomonocytic Leukemia and de Novo Myelodysplastic Syndrome, run by Mayo Clinic at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Azacitidine, Decitabine and Laboratory Biomarker Analysis
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
63 participants
Where
1 siteUnited States
Study dates
May 2014to 25 Oct 2019
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
Show all 39Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Mayo Clinic

    Rochester, Minnesota, 55905

Other trials in United States

About this study

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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Being tested
Azacitidine, Decitabine, Laboratory Biomarker Analysis, Quality-of-Life Assessment, Sonidegib
Medical subject headings
Leukemia, Myelomonocytic, Chronic, Thrombocythemia, Essential, Myelodysplastic Syndromes, Myelodysplastic-Myeloproliferative Diseases, Polycythemia Vera, Primary Myelofibrosis, Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AzacitidineDrug

    Also called 5 AZC, 5-AC, 5-Azacytidine, 5-AZC

    Given SC or IV

  • DecitabineDrug

    Also called 5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Quality-of-Life AssessmentOther

    Also called Quality of Life Assessment

    Ancillary studies

  • SonidegibDrug

    Also called ERISMODEGIB, LDE-225, LDE225, Odomzo

    Given PO

Study groups in NCT02129101
Study groupRoleWhat they receive
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.
Receives: Drug: Azacitidine; Drug: Decitabine; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Sonidegib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 30 days post-treatment

  2. 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.

    Measured: Up to 30 days post-treatment

  3. 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.

    Measured: Up to 30 days post-treatment

  4. 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.

    Measured: 42 days

Secondary outcomes (6)

  1. Duration of response

    The distribution of duration of response will be estimated using the method of Kaplan-Meier.

    Measured: 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

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

    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.

    Measured: Up to 30 days post-treatment

  3. Overall survival

    The distribution of survival time will be estimated using the method of Kaplan-Meier.

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

  4. Time to AML

    The distribution of time to AML will be estimated using the method of Kaplan-Meier.

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

  5. Time to death

    The distribution of time to death will be estimated using the method of Kaplan-Meier.

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

  6. Time to progression

    The distribution of time to progression will be estimated using the method of Kaplan-Meier.

    Measured: Time from registration to the earliest date of documentation of disease progression, assessed up to 30 days post-treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 May 2014 (estimated)
  2. Study startMay 2014
  3. Primary completion31 Dec 2016
  4. Study completion25 Oct 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
63 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02129101
Sponsor's protocol ID
MC1389
Other IDs
NCI-2014-00866, Mod13-009003-08, MC1389, P30CA015083
Status last verified
Aug 2019
First submitted
30 Apr 2014
Last updated
30 Oct 2019
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Azacitidine, Decitabine and Laboratory Biomarker Analysis in people with Chronic Myelomonocytic Leukemia and de Novo Myelodysplastic Syndrome, run by Mayo Clinic at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02129101.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Oct 2019.

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