Status and phase
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About
This phase II trial studies how well midostaurin and decitabine work in treating older patients with newly diagnosed acute myeloid leukemia and FLT3 mutations. Midostaurin and decitabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Full description
PRIMARY OBJECTIVES:
I. To determine the complete response rate for elderly patients with FLT3 mutated acute myeloid leukemia (AML) using midostaurin and decitabine.
SECONDARY OBJECTIVES:
I. Determine the 1-year overall survival (OS) and progression free survival (PFS) rates.
II. Determine overall response rates in patients treated with this regimen. III. Determine the complete response duration in patients treated with this regimen.
IV. Assess the safety and toxicity of this regimen based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
TERTIARY OBJECTIVES:
I. Assess the prognostic and predictive factors (FLT3 internal tandem duplication [ITD] versus [vs] tyrosine kinase domain [TKD] mutation) for patients treated with this regimen.
II. Explore genetic targets for this disease.
OUTLINE:
Patients receive decitabine intravenously (IV) over 1 hour on days 1-5 and midostaurin orally (PO) twice daily (BID) on days 8-21 of courses 1 and 2, and on days 1-28 of each subsequent course. Patients failing to achieve complete response (CR)/complete response with incomplete recovery (CRi)/partial response (PR)/morphologic leukemia-free state by end of course 2 receive midostaurin PO BID on days 1-28. Patients achieving CR/CRi/PR/morphologic leukemia-free state by end of course 8 may continue on current regimen. Patients failing to achieve a CR/CRi/PR/ morphologic leukemia-free state in bone marrow blasts by end of course 8 go to event monitoring. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 2 years.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Unfit for chemotherapy based on investigator assessment or patient not willing to receive intensive induction as advised by investigator
Untreated, histological confirmed acute myeloid leukemia (AML) based on World Health Organization (WHO) 2008 criteria with either/or both:
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2 or 3
Serum amylase and lipase =< 1.5 x upper limit of normal (ULN)
Total bilirubin =< 1.5 x ULN (does not apply to patients with isolated hyperbilirubinemia [e.g., Gilbert's disease], in that case direct bilirubin should be =< 2 x ULN)
Alkaline phosphatase =< 3 x ULN
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN
Creatinine =< 2 x ULN
Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
Provide informed written consent
Willing to return to consenting Mayo Clinic (Mayo Clinic's campus in Rochester), for follow-up during the Active Monitoring Phase of the study
Willing to provide bone marrow aspirate and blood samples for correlative research purposes
Exclusion criteria
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months after treatment completion
Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject; NOTE: periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
Female sterilization (have 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 sterilization (at least 6 months prior to screening); NOTE: for female subjects on the study the vasectomized male partner should be the sole partner for that subject
Combination of any two of the following (a+b or a+c, or b+c):
NOTE:
Sexually active males unless they use a condom during intercourse while taking drug and for 5 months after stopping midostaurin medication
NOTE:
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Immunocompromised patients (other than that related to the use of corticosteroids) including patients confirmed to be human immunodeficiency virus (HIV) positive or have active viral hepatitis
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements; patients with any other known concurrent severe and/or uncontrolled medical condition (except carcinoma in-situ), which could compromise participation in the study (e.g. uncontrolled infection, uncontrolled diabetes, chronic active pancreatitis)
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Other active malignancy =< 1 year prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix
Previous treatment with specific chemotherapy (cytarabine, idarubicin, daunorubicin) or hypomethylating drug (decitabine or azacitidine) for a hematological disorder; EXCEPTIONS: prior hydroxyurea allowed; secondary AML is allowed
Impaired cardiac function including any of the following:
Patients currently receiving treatment with strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and treatment that cannot be either discontinued or switched to a different medication prior to starting study drug; patients receiving any medications or substances that are strong inhibitors of CYP3A4; all azoles but fluconazole are discouraged to be used in patients requiring treatment with antifungal antibiotics; use of the following strong inhibitors is prohibited =< 7 days prior to registration
Strong inhibitors of CYP3A4/5; > 5-fold increase in the plasma area under the curve (AUC) values or more than 80% decrease in clearance
Receiving any medications or substances that are inducers of CYP3A4; use of the following inducers are prohibited =< 7 days prior to registration
Strong inducers of CYP3A4/5; > 80% decrease in AUC
Moderate inducers of CYP3A4/5; 50-80% decrease in AUC
Patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug; NOTE: prohibited medications contains drugs that should be used with caution due to possible or conditional risk of Torsades de Pointes
Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)
Acute or chronic pancreatic disease
Known cytopathologically confirmed central nervous system (CNS) infiltration
Acute or chronic liver disease or severe renal disease considered unrelated to the cancer
History of significant congenital or acquired bleeding disorder unrelated to cancer
Major surgery =< 4 weeks prior to registration of the study or who have not recovered from prior surgery regardless of time since surgery
Treatment with other investigational agents =< 30 days or 5 half-lives of registration
Diagnosis of AML-M3 (or acute promyelocytic leukemia)
Primary purpose
Allocation
Interventional model
Masking
1 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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