Phase Ib, Open Label, Combination Study of Nintedanib With 5-Azacitidine in Acute Myeloid Leukemia Characterized by HOX Gene Overexpression, That Are Not Candidates of Intensive Chemotherapy
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Northwestern University
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD)
Overview
Brief Summary
The purpose of this study is to find the appropriate dose of the study drug nintedanib when combined with azacitidine and the associated side effects of the combination in older adults with AML characterized by HOX gene overexpression who are not interested in or not considered fit for standard intensive chemotherapy. The use of the study drug nintedanib in this study is investigational. Investigational means that this medication has not yet been approved by the FDA to treat this type of cancer. Azacitidine received FDA Approval in 2004 for myelodysplastic syndrome (a blood cancer related to AML) and has a National Comprehensive Cancer Network (NCCN) guideline recommendation for treatment of older adults who are not candidates for or decline intensive remission induction therapy. We expect participation to continue in this study based on each participant's response to the drug, and ability to tolerate treatment. Participants may continue to receive study treatments for 6 cycles (one cycle is 28 days long). If the 6 cycles of treatment is completed, participants may be moved on to a maintenance phase of treatment. Treatment will continue until the participant's leukemia gets worse, or they experience serious side effects, have a break in treatment for more than 56 days or the study doctor feels it is best for study treatments to stop.
Detailed Description
PRIMARY OBJECTIVES:
I. To identify maximum tolerated dose (MTD) of nintedanib for combination treatment of nintedanib and azacytidine (5-azacitidine) in the treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia with HOX overexpression and who are ineligible for intensive chemotherapy.
SECONDARY OBJECTIVES:
I. Adverse events (AEs) including dose limiting toxicities (DLTs) will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
II. To determine median overall survival. III. To determine complete remission (CR) rate.
EXPLORATORY OBJECTIVES:
I. To determine composite CR rate (CR + complete remission with incomplete platelet recovery [CRp] + complete remission with incomplete hematological recovery [Cri]).
II. To determine duration of confirmed response. III. To determine event free survival. IV. To determine leukemia free survival. V. To establish correlation between response and pre-treatment Fgf2 levels and change in Fgf-2 levels during treatment.
OUTLINE: This is a dose-escalation study of azacitidine.
Participants receive nintedanib orally (PO) twice daily (BID) on days 1-28 and azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, participants may discontinue treatment, receive nintedanib every 4-8 weeks, or receive nintedanib and azacitidine every 4-8 weeks.
After completion of study treatment, participants are followed up at every 3 months for 12 months and then every 6 months for up to 24 months.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •ESCLATION COHORT: Patients must have a diagnosis of newly diagnosed and/ or relapsed/refractory AML with any of the following:
- •Confirmed translocation involving 11q23
- •Partial tandem duplication(PTD) of the MLL gene (on 11q23)
- •FLT3-ITD (internal tandem duplication)
- •Increased Fgf2 in serum (2 standard deviations above control serum samples)
- •HOX(A9/A10) over-expression in bone marrow ( 2 standard deviations above control values in CD34+ cells from normal subjects)
- •Note: Relapsed or refractory AML is defined as either:
- •Recurrence of disease after a complete remission (CR), or
- •Failure to achieve CR with initial therapy
- •EXPANSION COHORT: Patients must have a diagnosis of newly diagnosed AML with any of the following:
Exclusion Criteria
- •Patients who have received chemo-, hormone-, radio or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 14 days prior to start of treatment or those who have not recovered from adverse events attributed to the agent to grade 1 or baseline
- •Exceptions for prior treatments are:
- •Hydroxyurea for increased blast count (no washout period required; it can be continued throughout the first cycle of therapy)
- •Leukapheresis for leukocytosis (no wash out period required; it can be continued during the study)
- •Note: If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration; please see assigned quality assurance monitor (QAM) with questions
- •Patients who have received any other investigational product within14 days of treatment are not eligible for this study; a wash out period ? 14 days or 5 half- lives (whichever is greater) is required from investigational treatment, prior to start of study treatment; please Note:
- •If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration; please see assigned QAM with questions
- •The ?5 half-lives? time period will be determined by investigational pharmacy
- •If half life is not known and cannot be predicted, then wash out of ? 14 days is required
- •Patients who have had major injuries and/or surgery within the past 4 weeks (\< 28 days) prior to registration with incomplete wound healing and/or planned surgery while the patient is on study treatment
Arms & Interventions
Treatment (nintedanib, azacitidine)
Participants receive nintedanib PO BID on days 1-28 and azacitidine IV or SC on days 1-7. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, participants may discontinue treatment, receive nintedanib every 4-8 weeks, or receive nintedanib and azacitidine every 4-8 weeks.
Intervention: Azacitidine (Drug)
Treatment (nintedanib, azacitidine)
Participants receive nintedanib PO BID on days 1-28 and azacitidine IV or SC on days 1-7. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, participants may discontinue treatment, receive nintedanib every 4-8 weeks, or receive nintedanib and azacitidine every 4-8 weeks.
Intervention: Laboratory Biomarker Analysis (Other)
Treatment (nintedanib, azacitidine)
Participants receive nintedanib PO BID on days 1-28 and azacitidine IV or SC on days 1-7. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, participants may discontinue treatment, receive nintedanib every 4-8 weeks, or receive nintedanib and azacitidine every 4-8 weeks.
Intervention: Nintedanib (Drug)
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: Up to 28 days
Will be defined as the highest dose that causes dose limiting toxicities (DLTs) in \< 2 of 6 patients.
Secondary Outcomes
- Incidence of adverse events(Up to 24 months)
- Overall survival(Up to 24 months)
- Complete remission (CR) rate(Up to 24 months)