Clinical Trials /

Midostaurin and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia and FLT3 Mutation

NCT02634827

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Midostaurin and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia and FLT3 Mutation
  • Official Title: A Phase II Study of Combination Midostaurin and Decitabine (MIDDAC) in Elderly Patients Newly Diagnosed With Acute Myeloid Leukemia and FLT3 Mutation

Clinical Trial IDs

  • ORG STUDY ID: MC1483
  • SECONDARY ID: NCI-2015-02107
  • SECONDARY ID: MC1483
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT02634827

Conditions

  • Acute Myeloid Leukemia With FLT3/ITD Mutation
  • Acute Myeloid Leukemia With Gene Mutations
  • FLT3 Tyrosine Kinase Domain Point Mutation
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, midostaurin)
MidostaurinCGP 41251, CGP41251, N-Benzoyl-Staurosporine, N-Benzoylstaurosporine, PKC-412, PKC412Treatment (decitabine, midostaurin)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, midostaurin)ExperimentalPatients 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.
  • Decitabine
  • Midostaurin

Eligibility Criteria

        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:

               -  FLT3 ITD mutation

               -  FLT3 TKD mutation

          -  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):

                    -  a) Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate < 1%), for example hormone vaginal ring or transdermal hormone
                       contraception

                    -  b) Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    -  c) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository

               -  NOTE:

                    -  In case of use of oral contraception women should have been stable on the
                       same pill for a minimum of 3 months before taking study treatment

                    -  Women are considered post-menopausal and not of 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

               -  Sexually active males unless they use a condom during intercourse while taking
                  drug and for 5 months after stopping midostaurin medication

               -  NOTE:

                    -  They should not father a child in this period

                    -  A condom is required to be used also by vasectomized men in order to prevent
                       delivery of the drug via seminal fluid

          -  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:

               -  Inability to monitor the QT interval on electrocardiogram (ECG)

               -  Congenital long QT syndrome or a known family history of long QT syndrome

               -  Clinically significant resting brachycardia (< 50 beats per minute)

               -  Corrected QT (QTc) > 450 msec on baseline ECG; NOTE: if the ECG shows a QTc
                  interval greater than 450 msecs at screening triplicates should be performed, one
                  minute apart to confirm the finding (after replacement of any electrolyte
                  imbalance); if 2/3 or 3/3 of the ECGs confirm the QT prolongation (i.e. QTc
                  interval > 450 msecs) the patient must not be included into the trial

               -  Myocardial infarction =< 3 months prior to starting study

               -  Other clinically significant uncontrolled heart disease (e.g. unstable angina,
                  congestive heart failure or uncontrolled hypertension)

               -  History of or presence of clinically significant ventricular, atrial
                  tachyarrhythmias or ejection fraction cutoff

               -  Left ventricle ejection fraction < 45%

               -  History of congestive heart failure requiring use of ongoing maintenance therapy
                  for life-threatening ventricular arrhythmias

          -  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

                    -  Boceprevir (Victrelis)

                    -  Clarithromycin (Biaxin, Biaxin XL)

                    -  Conivaptan (Vaprisol)

                    -  Indinavir (Crixivan)

                    -  Itraconazole (Sporanox)

                    -  Ketoconazole (Nizoral)

                    -  Lopinavir/Ritonavir (Kaletra)

                    -  Mibefradil

                    -  Nefazodone (Serzone)

                    -  Nelfinavir (Viracept)

                    -  Posaconazole (Noxafil)

                    -  Ritonavir (Novir®, Kaletra)

                    -  Saquinivir (Fortovase, Invirase)

                    -  Telaprevir (Incivek)

                    -  Telithromycin (Ketek)

                    -  Voriconazole (Vfend)

                    -  Troleandomycin

                    -  Cobicistat

                    -  Tipranavir

          -  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

                    -  Avasimibe

                    -  Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR)

                    -  Phenytoin (Dilantin, Phenytek)

                    -  Rifampin (Rifadin)

                    -  St. John's wort

                    -  Mitotane

                    -  Rifabutin

                    -  Phenobarbital

               -  Moderate inducers of CYP3A4/5; 50-80% decrease in AUC

                    -  Bosentan (Tracleer)

                    -  Efavirenz (Sustiva)

                    -  Etravirine (Intelence)

                    -  Modafinil (Provigil)

                    -  Nafcillin

                    -  Genistein

                    -  Ritonavir

                    -  Talyiraline

                    -  Thioridazine

                    -  Tipranavir

                    -  Nevirapine (Viramune)

                    -  Phenobarbital (Luminal)

                    -  Rifabutin (Mycobutin)

                    -  Troglitazone

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:60 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of complete responses to therapy, where a success is defined as a CR or CRi as the objective status
Time Frame:Up to 2 years
Safety Issue:
Description:The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial confidence intervals for the true success proportion will be calculated.

Secondary Outcome Measures

Measure:Duration of complete response, defined for all evaluable patients who have achieved a CR or CRi as the date at which the patient's objective status is first noted to be a CR or CRi to the earliest date relapse is documented
Time Frame:Up to 2 year
Safety Issue:
Description:The distribution of duration of complete response will be estimated using the method of Kaplan-Meier. If there are a sufficient number of CR/CRi, a landmark analyses may be performed to compare duration of CR/CRi in patients who first achieved a CR/CRi at 2 months vs those who first achieved a CR/CRi at 8 months.
Measure:Incidence of adverse events, graded according to the NCI CTCAE version 4.0
Time Frame:Up to 2 years
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. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Measure:OS
Time Frame:Time from registration to death due to any cause, assessed up to 2 years
Safety Issue:
Description:Estimated using the method of Kaplan-Meier. In addition, the overall survival rate at 1 year after registration will be reported.
Measure:Overall response rate, estimated by the total number of complete or partial responses (CR, CRi, morphologic leukemia-free state, or PR) divided by the total number of evaluable patients
Time Frame:Up to 2 years
Safety Issue:
Description:Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
Measure:PFS
Time Frame:Time from registration to the time of relapse or death due to any cause, assessed up to 2 years
Safety Issue:
Description:Estimated using the method of Kaplan-Meier. In addition, the progression-free survival rate at 1 year after registration will be reported.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Mayo Clinic

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