Clinical trial NCT01846624: Decitabine and Midostaurin in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
Official title: A Phase 2 Study of Decitabine in Combination With Midostaurin (PKC412) for Elderly Patients With Newly Diagnosed FLT3-ITD/TKD Positive Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML) With Multilineage Dysplasia Following Myelodysplastic Syndrome, in Adults
AML (Adult) With 11q23 (MLL) Abnormalities
AML (Adult) With Del (5q)
AML (Adult) With Inv (16) (p13; q22)
AML (Adult) With t (16;16) (p13; q22)
AML (Adult) With t (8; 21) (q22; q22)
Secondary AML (Adult)
Untreated AML (Adult)
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2013-05-03
Enrollment: 13
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase 2 study evaluates the sequential combination of decitabine then midostaurin for the treatment of newly-diagnosed acute myeloid leukemia (AML) in older patients.

Detailed description: Treatment with decitabine, a cytidine analog, then midostaurin, a multi-target protein kinase inhibitor (PKI), may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Eligibility criteria: Inclusion Criteria:

* Newly-diagnosed acute myeloid leukemia (AML) per the World Health Organization \[WHO\] 2008 classification \[except t (15; 17)\], including:

  * De novo AML
  * Secondary AML
  * Secondary AML arising from previously-diagnosed myelodysplastic syndromes (MDS) treated with deoxyribonucleic acid (DNA) methyltransferase inhibitor (DNMTi) (ie, decitabine or azacitidine)
* FLT3-ITD mutation confirmed in bone marrow aspirate
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
* Serum bilirubin ≤ 2.5 ULN
* Serum creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 50 mL/min
* Ejection fraction ≥ 50% by echocardiogram
* Unwillingness or inability to receive conventional chemotherapy
* Ability to understand and the willingness to sign a written informed consent document
* Ability to adhere to the study visit schedule and other protocol requirements
* Life expectancy \> 2 months

Exclusion Criteria:

* Receiving concomitant treatment with other anti-neoplastic agents (EXCEPTION: hydroxyurea). Prior treatment with DNMTi therapy (ie, decitabine or azacitidine) for MDS is allowed
* Received anti-neoplastic treatment within 4 weeks prior to enrollment (EXCEPTION: hydroxyurea)
* Received any surgical procedure, excluding central venous catheter placement or other minor procedures (eg, skin biopsy) within 14 days of study day 1
* Received any investigational agent within 4 weeks prior to enrollment
* Previous or current history of a myeloproliferative disease
* Known active central nervous system (CNS) malignancy
* Any other known disease (except carcinoma in-situ), concurrent severe and/or uncontrolled medical condition which could compromise participation in the study (eg, uncontrolled diabetes; cardiovascular disease including congestive heart failure; myocardial infarction within 6 months with poorly controlled hypertension; chronic renal disease; active uncontrolled infection)
* Active opportunistic infection or treatment for opportunistic infection within 4 weeks of first day of study drug dosing
* Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active viral hepatitis
* Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of midostaurin
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to midostaurin and/or decitabine
* Impaired cardiac function including any of the following:

  * Screening electrocardiogram (ECG) with a corrected QT interval (QTc) \> 450 msec
  * Bradycardia defined as heart rate (HR) \< 50 beats per minute (bpm)
  * Right bundle branch block + left anterior hemiblock (bifascicular block)
  * Patients with myocardial infarction or unstable angina \< 3 months prior to starting study drug
  * Congestive heart failure (CHF) New York (NY) Heart Association class 3 or 4
* Inability to swallow or absorb drug
* Other medical or psychiatric illness or organ dysfunction or laboratory abnormality which in the opinion of the investigator would compromise the patient's safety or interfere with data interpretation
* Unwillingness or inability to comply with the protocol
* Pregnant
* nursing (lactating)
* 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 midostaurin medication; highly effective contraception methods as follows:

  * Total abstinence, when this is in line with the preferred and usual lifestyle of the subject \[periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception\]
  * Female sterilization (surgical bilateral oophorectomy with or without hysterectomy; or tubal ligation at least six weeks before taking study treatment). In case of oophorectomy alone, reproductive status must be confirmed by follow-up hormone level assessment
  * Male sterilization, at least 6 months prior to screening (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):

    * Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), eg, hormone vaginal ring or transdermal hormone contraception. For oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment
    * Placement of an intrauterine device (IUD) or intrauterine system (IUS)
    * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

Primary outcomes:
measure: Complete Remission (CR) Rate
timeFrame: Up to 1 year
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: up to 1 year
measure: Median Duration of Response (DoR)
timeFrame: Up to 1 year
measure: Progression-free Survival (PFS)
timeFrame: Up to 2 years
measure: Overall Survival (OS)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: David J Iberri, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lowenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74. doi: 10.1182/blood-2009-07-235358. Epub 2009 Oct 30.