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A Randomized Phase III Study of Standard Cytarabine Plus Daunorubicin (7+3) Therapy or Idarubicin With High Dose Cytarabine (IA) Versus IA With Vorinostat (NSC-701852) (IA+V) in Younger Patients With Previously Untreated Acute Myeloid Leukemia (AML)


Phase 3
18 Years
60 Years
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

A Randomized Phase III Study of Standard Cytarabine Plus Daunorubicin (7+3) Therapy or Idarubicin With High Dose Cytarabine (IA) Versus IA With Vorinostat (NSC-701852) (IA+V) in Younger Patients With Previously Untreated Acute Myeloid Leukemia (AML)


PRIMARY OBJECTIVES:

I. To compare event-free survival (EFS) between patients with acute myeloid leukemia (AML)
who receive standard 7+3 (cytarabine and daunorubicin hydrochloride) or idarubicin and
high-dose cytarabine (IA) to patients who receive IA + vorinostat. (Chemotherapy) II. To
determine whether it is possible to get 60% or more of adults with high-risk AML in first
complete remission (CR1) to allogeneic hematopoietic cell transplantation (HCT).
(Transplant)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the three regimens in this
patient population. (Chemotherapy) II. To estimate disease-free survival (DFS) among
patients who receive transplant. (Transplant) III. To compare event-free survival (EFS)
between patients who receive standard 7+3 to patients who receive IA. (Chemotherapy) IV. To
estimate the prevalence of the mutations nucleophosmin (nucleolar phosphoprotein B23,
numatrin) (NPM1), isocitrate dehydrogenase 1 (NADP+), soluble (IDH1), isocitrate
dehydrogenase 2 (NADP+), mitochondrial (IDH2), tet methylcytosine dioxygenase 2 (TET2) and
DMT3A and the cytogenetic risk distribution of patients on this study and to evaluate the
association between these and overall survival (OS), EFS, DFS, and complete remission rate.
(Chemotherapy/Translational Medicine) V. To compare the complete response rate, DFS, and OS
between patients who receive standard 7+3 therapy or IA to patients who receive IA +
vorinostat. (Chemotherapy)

TERTIARY OBJECTIVES:

I. Future planned studies will include testing of histone H3 acetylation, induction of gamma
H2A histone family, member X (H2AX), analysis of reactive oxygen species (ROS) resistance
and deoxyribonucleic acid (DNA) methylation profiles. (Chemotherapy/Translational Medicine)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

INDUCTION/RE-INDUCTION:

ARM I: Patients receive standard dose cytarabine intravenously (IV) continuously on days 1-7
and daunorubicin hydrochloride IV on days 1-3. Patients with residual blasts may receive
re-induction treatment beginning on day 15. Patients achieving complete remission (CR) or
complete remission with incomplete platelet recover (CRi) may proceed to allogeneic
hematopoietic stem cell transplant (HSCT) or to consolidation therapy.

ARM II: Patients receive high dose cytarabine IV continuously on days 1-4 and idarubicin IV
over 15 minutes on days 1-3. Patients with residual blasts may receive re-induction
treatment beginning on day 28. Patients achieving CR or CRi may proceed to allogeneic HSCT
or to consolidation therapy.

ARM III: Patients receive vorinostat orally (PO) thrice daily (TID) on days 1-3, high-dose
cytarabine IV continuously on days 4-7, and idarubicin IV over 15 minutes on days 4-6.
Patients with residual blasts may receive re-induction treatment beginning on day 28.
Patients achieving CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.

CONSOLIDATION:

ARM I: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5.

ARM II: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15
minutes on days 1-2.

ARM III: Patients receive vorinostat PO TID on days 1-3, cytarabine IV continuously on days
4-6, and idarubicin IV over 15 minutes on days 4-5.

In all arms, treatment repeats every 28 days for 4 courses or until transplant in the
absence of disease progression or unacceptable toxicity.

TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or
consolidation therapy.

After completion of study treatment, patients are followed for every 3 months for 1 year,
every 6 months for 2 years, and then annually for 2 years.


Inclusion Criteria:



- STEP 1 - INDUCTION/RE-INDUCTION

- Patients must have morphologically confirmed newly diagnosed acute myelogenous
leukemia (AML); Note: this protocol uses World Health Organization (WHO) diagnostic
criteria for AML; patients with acute promyelocytic leukemia (APL,
French-American-British [FAB], M3) or blastic transformation of chronic myelogenous
leukemia (CML) are not eligible; patients with known core binding factor (CBF) or
fms-like tyrosine kinase 3 (FLT3) related leukemias are eligible for this study, but
should preferentially be placed on National Cancer Institute (NCI)-sponsored
protocols specific for these subtypes, if available

- Patients must have diagnostic/pre-treatment specimens obtained within 28 days prior
to registration submitted to the site's local Clinical Laboratory Improvement
Amendments (CIA)-approved laboratory for cytogenetic (and fluorescent in situ
hybridization [FISH] if possible) analysis to determine risk status; high risk
classification will be defined as del(5q)/-5, del(7q)/-7, abn3q26 [inv(3)/t(3;3)],
11q23 rearrangement [except t(9;11)], 17p-, t(6;9), t(9;22), complex (at least 3
unrelated abnormalities [abn]), and monosomal karyotype (either loss of two different
chromosomes or loss of one chromosome along with a structural chromosome abnormality
other than add, ring and mar); karyograms and cytogenetics/FISH analysis reports must
be submitted for discipline review

- Patients must be chemo-naïve, i.e., not have received any prior Induction
chemotherapy for AML or myelodysplastic syndrome (MDS); temporary prior measures such
as apheresis or hydroxyurea are allowed; prior anthracycline therapy is allowed, but
must not exceed a dose of 200 mg/m^2 daunorubicin or equivalent; patients with prior
history of MDS must not have received azacitidine, decitabine, lenalidomide or
vorinostat

- Patients must have peripheral blood and bone marrow aspirate specimens obtained
within 28 days prior to registration submitted for translational medicine; with
patient consent, residuals will be banked for future research

- Patients must have Zubrod performance status =< 3

- Patients must have either echocardiogram (ECHO) or multi gated acquisition scan
(MUGA) with ejection fraction >= 45% within 28 days prior to registration

- Patients must not have prolonged QTc interval (> 500 msec) determined by
electrocardiogram (EKG) within 28 days prior to registration

- Patients must not have cardiac disease defined as: New York Heart Association (NYHA)
> class II; patients must not have unstable angina (angina symptoms at rest) or new
onset angina (began within the last 3 months) or myocardial infarction within the
past 6 months

- Patients must not have any coexisting medical condition that is likely to interfere
with study procedures or results, and must be reasonable candidates for intensive
chemotherapy, in the opinion of their treating physicians

- Patients who are known to be human immunodeficiency virus (HIV) positive (+) are
eligible providing they meet all of the following additional criteria within 28 days
prior to registration:

- Cluster of differentiation (CD) 4 cells >= 500/mm^3

- Viral load < 50 copies of HIV messenger ribonucleic acid (mRNA)/mm^3 if on
combination antiretroviral therapy (cART) or < 25,000 copies of HIV mRNA if not
on cART

- No zidovudine or stavudine as part of cART; patients who are HIV+ and do not
meet all of these criteria are not eligible for this study

- Patients with known hepatitis B or hepatitis C infection may be eligible providing
they have viral load < 800,000 IU/L within 28 days prior to registration

- Patients must be able to take oral medications

- Patients must not be pregnant or nursing due to the teratogenic potential of the
drugs used in this study; women/men of reproductive potential must have agreed to use
an effective contraceptive method; a woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months;
in addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a
side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
oophorectomy or bilateral tubal ligation; however, if at any point a previously
celibate patient chooses to become heterosexually active during the time period for
use of contraceptive measures outlined in the protocol, he/she is responsible for
beginning contraceptive measures

- Prior malignancy is allowed providing it does not require concurrent therapy;
exception: active hormonal therapy is allowed

- Patients must not be receiving valproic acid

- All patients must be informed of the investigational nature of this study; patients
or a legally authorized representative must sign and give written informed consent in
accordance with institutional and federal guidelines

- STEP 2 - CONSOLIDATION

- Patients may be registered for Consolidation provided that they were eligible for the
initial Induction/Re-Induction registration and satisfy the following additional
criteria:

- Patients must have achieved morphologic remission (complete remission [CR] or
complete remission with incomplete platelet recover [CRi]) after completion of
Induction or Re-Induction therapy; patient must remain in remission until
beginning Consolidation and this must be documented by bone marrow and
peripheral blood examination within 28 days prior to registration to Step 2

- All non-hematologic treatment related toxicities that are deemed clinically
significant by the treating physician must have resolved to =< grade 2

- Patients must not have received allogeneic stem cell transplant

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

EFS

Outcome Time Frame:

Up to 5 years

Safety Issue:

No

Principal Investigator

Guillermo Garcia-Manero

Investigator Role:

Principal Investigator

Investigator Affiliation:

Southwest Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00490

NCT ID:

NCT01802333

Start Date:

February 2013

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Cleveland Clinic FoundationCleveland, Ohio  44195
Washington University School of MedicineSaint Louis, Missouri  63110
Loyola University Medical CenterMaywood, Illinois  60153
LDS HospitalSalt Lake City, Utah  84143
Eastern Maine Medical CenterBangor, Maine  04401
Via Christi Regional Medical CenterWichita, Kansas  67214
Wesley Medical CenterWichita, Kansas  67214
Great Falls ClinicGreat Falls, Montana  59405
Cancer Center of Kansas - ChanuteChanute, Kansas  66720
Cancer Center of Kansas - Dodge CityDodge City, Kansas  67801
Cancer Center of Kansas - NewtonNewton, Kansas  67114
Cancer Center of Kansas - SalinaSalina, Kansas  67042
Cancer Center of Kansas - WellingtonWellington, Kansas  67152
Associates in Womens HealthWichita, Kansas  67203
Cancer Center of Kansas - WinfieldWinfield, Kansas  67156
Bozeman Deaconess HospitalBozeman, Montana  59715
Kalispell Regional Medical CenterKalispell, Montana  59901
American Fork HospitalAmerican Fork, Utah  84003
Logan Regional HospitalLogan, Utah  84321
McKay-Dee Hospital CenterOgden, Utah  84403
Welch Cancer CenterSheridan, Wyoming  82801
Grandview HospitalDayton, Ohio  45405
Mountainview MedicalBerlin, Vermont  05602
Miami Valley HospitalDayton, Ohio  45409
Cancer Center of Kansas - Fort ScottFort Scott, Kansas  66701
Cancer Center of Kansas-IndependenceIndependence, Kansas  67301
Lawrence Memorial HospitalLawrence, Kansas  66044
Wayne HospitalGreenville, Ohio  45331
Rocky Mountain OncologyCasper, Wyoming  82609
Greene Memorial HospitalXenia, Ohio  45385
Harold Alfond Center for Cancer CareAugusta, Maine  04330
Memorial Medical CenterSpringfield, Illinois  62781
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
University of RochesterRochester, New York  14642
Wayne State UniversityDetroit, Michigan  48202
University of Arizona Health Sciences CenterTucson, Arizona  85724
Cancer Center of Kansas - McPhersonMcPherson, Kansas  67460
University Of VermontBurlington,, Vermont  05403
University of KentuckyLexington, Kentucky  40536-0098
Wichita CCOPWichita, Kansas  67214-3882
Montana Cancer Consortium CCOPBillings, Montana  59101
Decatur Memorial HospitalDecatur, Illinois  62526
Montana Cancer SpecialistsMissoula, Montana  59807-7877
Reid Hospital and Health Care ServicesRichmond, Indiana  47374
Mercy Medical Center-Sioux CitySioux City, Iowa  51104
Saint Luke's Regional Medical CenterSioux City, Iowa  51104
Cancer Center of Kansas - El DoradoEl Dorado, Kansas  67042
Cancer Center of Kansas-KingmanKingman, Kansas  67068
Cancer Center of Kansas - ParsonsParsons, Kansas  67357
Cancer Center of Kansas - PrattPratt, Kansas  67124
Cancer Center of Kansas-Wichita Medical Arts TowerWichita, Kansas  67208
Cancer Center of Kansas - Main OfficeWichita, Kansas  67214
Hematology-Oncology Centers of the Northern Rockies PCBillings, Montana  59101
Saint Vincent HealthcareBillings, Montana  59101
Billings ClinicBillings, Montana  59107-7000
Saint James Community Hospital and Cancer Treatment CenterButte, Montana  59701
Benefis Healthcare- Sletten Cancer InstituteGreat Falls, Montana  59405
Saint Peter's Community HospitalHelena, Montana  59601
Saint Patrick Hospital - Community HospitalMissoula, Montana  59802
Kinston Medical Specialists PAKinston, North Carolina  28501
Summa Barberton HospitalBarberton, Ohio  44203
Good Samaritan Hospital - DaytonDayton, Ohio  45406
Dayton CCOPDayton, Ohio  45429
Samaritan North Health CenterDayton, Ohio  45415
Blanchard Valley HospitalFindlay, Ohio  45840
Atrium Medical Center-Middletown Regional HospitalFranklin, Ohio  45005-1066
Kettering Medical CenterKettering, Ohio  45429
Upper Valley Medical CenterTroy, Ohio  45373
Cancer Center of Kansas-LiberalLiberal, Kansas  67901
Sandra L Maxwell Cancer CenterCedar City, Utah  84720
Intermountain Medical CenterMurray, Utah  84157
Utah Valley Regional Medical CenterProvo, Utah  84603
Dixie Medical Center Regional Cancer CenterSaint George, Utah  84770
Utah Cancer Specialists-Salt Lake CitySalt Lake City, Utah  84106
Arizona Cancer Center at University Medical Center NorthTucson, Arizona  85719
Stanford University Hospitals and ClinicsStanford, California  94305
Siouxland Hematology Oncology AssociatesSioux City, Iowa  51101
Summa Akron City HospitalAkron, Ohio  44304
Franciscan St. Francis HealthIndianapolis, Indiana  46237
Southwest Oncology GroupSan Antonio, Texas  78245