Chronic Myelomonocytic LeukemiaPhase 1NCT02553941
Ibrutinib and Azacitidine for Treatment of Higher Risk Myelodysplastic Syndrome
A Phase 1 study testing Azacitidine and Ibrutinib in people with Chronic Myelomonocytic Leukemia and de Novo Myelodysplastic Syndrome, run by Brian Jonas at 5 sites in United States.
Trial summary
This phase Ib trial studies the side effects and best dose of ibrutinib when given together with azacitidine in treating patients with myelodysplastic syndrome that is likely to occur or spread (higher risk) and who were previously treated or untreated and unfit for or refused intense therapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome
- What is being tested?
- Azacitidine and Ibrutinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 5 sitesUnited States
- Study dates
- 17 May 2016to 7 Nov 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
- Pathologically confirmed diagnosis of myelodysplastic syndrome
- Revised international prognostic scoring system (IPSS-R) intermediate, high or very high
- For the dose escalation cohorts, any prior number of MDS therapies, including hypomethylating agents, are permitted; for the dose expansion cohort, subjects must be azacitidine naïve, but otherwise any prior number of MDS therapies are permitted; treatment naïve patients are eligible for both the dose escalation and expansion cohorts if they are unfit for or refuse intense therapy
- No specific hematologic parameters for study entry are required; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm^3
- Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 x upper limit of normal (ULN)
- Estimated creatinine clearance >= 30 ml/min (Cockcroft-Gault)
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- Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN
- Karnofsky performance status (KPS) performance status of 60% or greater
- Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); or, female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
- Male and female subjects who agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of study drug
Who cannot join
- Known bleeding disorders, active bleeding disorders or clinical signs of bleeding (grade >= 2)
- Prior bone marrow transplant within 3 months or with acute graft versus host disease (GVHD)
- Prior treatment with a Bruton's tyrosine kinase (BTK) inhibitor
- Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives prior to first dose of study drug
- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
- History of other malignancies, except:
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- Malignancy treated with curative intent and with no known active disease present for >= 1 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- Low-risk prostate cancer after curative surgery
- Concurrent systemic immunosuppressant therapy
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
- Recent infection requiring intravenous systemic treatment
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment
- Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
- Major surgery within 4 weeks of first dose of study drug
- Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
- Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
- Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
- Concomitant use of warfarin or other vitamin K antagonists
- Requires treatment with a strong cytochrome P450 (CYP) family 3, subfamily A, polypeptide 4/5 (3A4/5) inhibitor
- Lactating or pregnant
- Unwilling or unable to participate in all required study evaluations and procedures
- Unable to understand informed consent form (ICF)
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, 90095
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
University of California San Diego
San Diego, California, 92103
University of California, San Francisco
San Francisco, California, 94118
About this study
Official title: Phase 1b Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes in Previously Treated Patients or in Untreated Patients Unfit for or Who Refuse Intense Therapy
This phase Ib trial studies the side effects and best dose of ibrutinib when given together with azacitidine in treating patients with myelodysplastic syndrome that is likely to occur or spread (higher risk) and who were previously treated or untreated and unfit for or refused intense therapy. Ibrutinib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Read the detailed description
PRIMARY OBJECTIVES:
- To evaluate the safety and tolerability of ibrutinib in combination with azacitidine in patients with higher risk myelodysplastic syndrome (MDS) and to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose of ibrutinib combined with azacitidine.
SECONDARY OBJECTIVES:
- To do an early assessment of the efficacy of the combination of ibrutinib and azacitidine in higher risk MDS. Specific secondary endpoints include: disease response per modified International Working Group (IWG) 2006 response criteria for MDS, hematologic normalization rate (HNR = complete remission [CR] + partial remission [PR] + hematologic improvement [HI]), overall survival (OS), progression free survival (PFS), disease free survival (DFS), and time to response (TTR).
TERTIARY OBJECTIVES:
- To evaluate the pharmacodynamic and biological effects and impact of quality of life (QoL) of the combination of ibrutinib and azacitidine in patients with higher risk MDS is the exploratory objective of this study. Exploratory endpoints include: laboratory biomarker analysis and effect on QoL assessments.
OUTLINE: This is a dose-escalation study of ibrutinib.
Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) once daily (QD) on days 1-7 or 1-5 and 8-9, and ibrutinib orally (PO) QD on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 6 months.
- Conditions
- Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome, Refractory Anemia With Excess Blasts in Transformation, Secondary Myelodysplastic Syndrome
- Being tested
- Azacitidine, Ibrutinib
- Medical subject headings
- Leukemia, Myelomonocytic, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Also called Vidaza
Given intravenous or subcutaneous
IbrutinibDrug
Also called BTK Inhibitor
Given by mouth once daily
| Study group | Role | What they receive |
|---|---|---|
| azacitidine, ibrutinib | Experimental | Patients receive azacitidine intravenous infusion over 10-40 minutes or subcutaneous on days 1-7 or 1-5 and 8-9, and ibrutinib by mouth one daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Receives: Drug: Azacitidine; Drug: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events
For each adverse event, the percentage of subjects who experience at least 1 occurrence of the given event will be summarized.
Measured: Within 30 days following the last dose of study drug or the first date starting new anticancer therapy
Secondary outcomes (5)
Disease Free Survival
For subjects achieving a Complete Response, Disease Free Survival will be calculated to determine durability of response. Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. Time-to-event data will be summarized descriptively by life-table statistics (median time to event; Kaplan-Meier plots).
Measured: From the time of first documented Complete Response until relapse or the date of death from any cause, assessed up to 6 months post-treatment
Disease response per modified International Working Group (IWG) 2006 response criteria for MDS
Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables.
Measured: Up to 96 weeks
HNR, defined as the proportion of treated subjects who achieve a CR, PR or HI as best response as assessed by the investigator and as defined by the modified IWG 2006 response criteria for MDS
Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables.
Measured: Up to 96 weeks
Overall survival
Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. Time-to-event data will be summarized descriptively by life-table statistics (median time to event; Kaplan-Meier plots).
Measured: From the time of first study drug administration until the date of death from any cause, assessed up to 6 months post-treatment
Progression Free Survival
Descriptive statistics will be used, including mean, standard deviation, median, and minimum and maximum values for continuous variables and frequencies and percentages for categorical variables. Time-to-event data will be summarized descriptively by life-table statistics (median time to event; Kaplan-Meier plots).
Measured: From the time of first study drug administration until the date of progression or death from any cause, assessed up to 6 months post-treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Sep 2015 (estimated)
- Study start17 May 2016
- Primary completion25 May 2019
- Study completion7 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Myelomonocytic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brian Jonas
- Sponsor type
- University, hospital or other
- Collaborators
- Pharmacyclics LLC.
- Responsible party
- Sponsor-investigator, Brian Jonas, University of California, Davis
- Investigators
- Brian Jonas, Principal investigator, University of California, Davis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02553941
- Sponsor's protocol ID
- 755461
- Other IDs
- UCDCC#256, PCI-32765, UCDCC#256
- Status last verified
- Oct 2022
- First submitted
- 27 Jul 2015
- Last updated
- 6 Oct 2022
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1b Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes in Previously Treated Patients or in Untreated Patients Unfit for or Who Refuse Intense Therapy
- ClinicalTrials.gov ID
- NCT02553941
- Acronym / sponsor ID
- 755461
- Conditions
- Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Previously Treated Myelodysplastic Syndrome, Refractory Anemia With Excess Blasts in Transformation, Secondary Myelodysplastic Syndrome
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Brian JonasUniversity, hospital or other
- Collaborators
- Pharmacyclics LLC.
- Study start
- 17 May 2016 (actual)
- Primary completion
- 25 May 2019 (actual)
- Study completion
- 7 Nov 2019 (actual)
- First posted
- 18 Sep 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase Ib trial studies the side effects and best dose of ibrutinib when given together with azacitidine in treating patients with myelodysplastic syndrome that is likely to occur or spread (higher risk) and who were previously treated or untreated and unfit for or refused intense therapy. Ibrutinib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES:
- To evaluate the safety and tolerability of ibrutinib in combination with azacitidine in patients with higher risk myelodysplastic syndrome (MDS) and to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose of ibrutinib combined with azacitidine.
SECONDARY OBJECTIVES:
- To do an early assessment of the efficacy of the combination of ibrutinib and azacitidine in higher risk MDS. Specific secondary endpoints include: disease response per modified International Working Group (IWG) 2006 response criteria for MDS, hematologic normalization rate (HNR = complete remission [CR] + partial remission [PR] + hematologic improvement [HI]), overall survival (OS), progression free survival (PFS), disease free survival (DFS), and time to response (TTR).
TERTIARY OBJECTIVES:
- To evaluate the pharmacodynamic and biological effects and impact of quality of life (QoL) of the combination of ibrutinib and azacitidine in patients with higher risk MDS is the exploratory objective of this study. Exploratory endpoints include: laboratory biomarker analysis and effect on QoL assessments.
OUTLINE: This is a dose-escalation study of ibrutinib.
Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) once daily (QD) on days 1-7 or 1-5 and 8-9, and ibrutinib orally (PO) QD on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 6 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| azacitidine, ibrutinib | Experimental | Drug: Azacitidine, Drug: IbrutinibPatients receive azacitidine intravenous infusion over 10-40 minutes or subcutaneous on days 1-7 or 1-5 and 8-9, and ibrutinib by mouth one daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Pathologically confirmed diagnosis of myelodysplastic syndrome
- Revised international prognostic scoring system (IPSS-R) intermediate, high or very high
- For the dose escalation cohorts, any prior number of MDS therapies, including hypomethylating agents, are permitted; for the dose expansion cohort, subjects must be azacitidine naïve, but otherwise any prior number of MDS therapies are permitted; treatment naïve patients are eligible for both the dose escalation and expansion cohorts if they are unfit for or refuse intense therapy
- No specific hematologic parameters for study entry are required; transfusion-dependent patients are eligible and platelet counts should be maintained greater than 10,000/mm^3
- Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 x upper limit of normal (ULN)
Key exclusion criteria (24 listed)
- Known bleeding disorders, active bleeding disorders or clinical signs of bleeding (grade >= 2)
- Prior bone marrow transplant within 3 months or with acute graft versus host disease (GVHD)
- Prior treatment with a Bruton's tyrosine kinase (BTK) inhibitor
- Anticancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives prior to first dose of study drug
- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzacitidineAlso: VidazaGiven intravenous or subcutaneous | Drug | azacitidine, ibrutinib |
| IbrutinibAlso: BTK InhibitorGiven by mouth once daily | Drug | azacitidine, ibrutinib |
Primary outcome
Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events
Time frame: Within 30 days following the last dose of study drug or the first date starting new anticancer therapy
For each adverse event, the percentage of subjects who experience at least 1 occurrence of the given event will be summarized.
5 secondary outcomes
Disease Free Survival
Time frame: From the time of first documented Complete Response until relapse or the date of death from any cause, assessed up to 6 months post-treatment
Disease response per modified International Working Group (IWG) 2006 response criteria for MDS
Time frame: Up to 96 weeks
HNR, defined as the proportion of treated subjects who achieve a CR, PR or HI as best response as assessed by the investigator and as defined by the modified IWG 2006 response criteria for MDS
Time frame: Up to 96 weeks
Overall survival
Time frame: From the time of first study drug administration until the date of death from any cause, assessed up to 6 months post-treatment
Progression Free Survival
Time frame: From the time of first study drug administration until the date of progression or death from any cause, assessed up to 6 months post-treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brian Jonas principal investigator
University of California, Davis
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Azacitidine and Ibrutinib in people with Chronic Myelomonocytic Leukemia and de Novo Myelodysplastic Syndrome, run by Brian Jonas at 5 sites 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 11 inclusion and 24 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 6 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites 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?
Incidence of toxicity of ibrutinib and azacitidine, graded according to the Common Terminology Criteria for Adverse Events (time frame: Within 30 days following the last dose of study drug or the first date starting new anticancer therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 6 Oct 2022.