Cytarabine and Daunorubicin Hydrochloride or Idarubicin and Cytarabine With or Without Vorinostat in Treating Younger Patients With Previously Untreated Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01802333
• Collaborator: (none)
• Enrollment: 754
• Locations: 447
• Arms: 3
• Duration (Months): 52
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or idarubicin and cytarabine with or without vorinostat to see how well they work in treating younger patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin hydrochloride, idarubicin, and vorinostat, work in different ways to stop the growth of cancer cells, either by killing the cells, stopping them from dividing, or by stopping from spreading. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells. It is not yet known which combination chemotherapy is more effective in treating acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cytarabine; Drug: Daunorubicin Hydrochloride; Drug: Idarubicin; Other: Laboratory Biomarker Analysis; Drug: Vorinostat	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. 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 (by cytogenetics) in first complete remission (CR1) to allogeneic hematopoietic cell transplantation (HCT). (Transplant)

SECONDARY OBJECTIVES:

1. 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 deoxyribonucleic acid (DNA) (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) and the cytogenetic risk distribution of patients on this study and to evaluate the association between these and overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and complete remission rate. (Chemotherapy/Translational Medicine) V. To compare the complete response rate, disease-free survival (DFS), and overall survival (OS) between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. (Chemotherapy)

TERTIARY OBJECTIVES:

1. 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 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. (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III may continue treatment without vorinostat.

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. (Permanently closed to accrual, effective 6/2/2015) Patient previously randomized to Arm III may continue treatment with or without vorinostat.

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 up every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 754 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Feb 12, 2013
• Actual Primary Completion Date: Jun 15, 2017
• Actual Study Completion Date: Jun 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (standard dose cytarabine, daunorubicin hydrochloride) INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic transplant; Other Names: Allogeneic Hematopoietic Cell Transplantation allogeneic stem cell transplantation HSC HSCT ; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-.beta.-D-Arabinofuranosylcytosine 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-Beta-D-arabinofuranosylcytosine 1.beta.-D-Arabinofuranosylcytosine 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl- 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl- Alexan Ara-C ARA-cell Arabine Arabinofuranosylcytosine Arabinosylcytosine Aracytidine Aracytin Aracytine Beta-cytosine Arabinoside CHX-3311 Cytarabinum Cytarbel Cytosar Cytosar-U Cytosine Arabinoside Cytosine-.beta.-arabinoside Cytosine-beta-arabinoside Erpalfa Starasid Tarabine PFS U 19920 U-19920 Udicil WR-28453 ; Drug: Daunorubicin Hydrochloride; Given IV; Other Names: Cerubidin Cerubidine Cloridrato de Daunorubicina Daunoblastin Daunoblastina Daunoblastine Daunomycin hydrochloride Daunomycin, hydrochloride Daunorubicin.HCl Daunorubicini Hydrochloridum FI-6339 Ondena RP-13057 Rubidomycin Hydrochloride Rubilem ; Other: Laboratory Biomarker Analysis; Correlative studies
Experimental: Arm II (high-dose cytarabine, idarubicin) INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic transplant; Other Names: Allogeneic Hematopoietic Cell Transplantation allogeneic stem cell transplantation HSC HSCT ; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-.beta.-D-Arabinofuranosylcytosine 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-Beta-D-arabinofuranosylcytosine 1.beta.-D-Arabinofuranosylcytosine 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl- 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl- Alexan Ara-C ARA-cell Arabine Arabinofuranosylcytosine Arabinosylcytosine Aracytidine Aracytin Aracytine Beta-cytosine Arabinoside CHX-3311 Cytarabinum Cytarbel Cytosar Cytosar-U Cytosine Arabinoside Cytosine-.beta.-arabinoside Cytosine-beta-arabinoside Erpalfa Starasid Tarabine PFS U 19920 U-19920 Udicil WR-28453 ; Drug: Idarubicin; Given IV; Other Names: 4-Demethoxydaunomycin 4-demethoxydaunorubicin 4-DMDR ; Other: Laboratory Biomarker Analysis; Correlative studies
Experimental: Arm III (vorinostat, high-dose cytarabine, idarubicin) INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic transplant; Other Names: Allogeneic Hematopoietic Cell Transplantation allogeneic stem cell transplantation HSC HSCT ; Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-.beta.-D-Arabinofuranosylcytosine 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-Beta-D-arabinofuranosylcytosine 1.beta.-D-Arabinofuranosylcytosine 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl- 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl- Alexan Ara-C ARA-cell Arabine Arabinofuranosylcytosine Arabinosylcytosine Aracytidine Aracytin Aracytine Beta-cytosine Arabinoside CHX-3311 Cytarabinum Cytarbel Cytosar Cytosar-U Cytosine Arabinoside Cytosine-.beta.-arabinoside Cytosine-beta-arabinoside Erpalfa Starasid Tarabine PFS U 19920 U-19920 Udicil WR-28453 ; Drug: Idarubicin; Given IV; Other Names: 4-Demethoxydaunomycin 4-demethoxydaunorubicin 4-DMDR ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vorinostat; Given PO; Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza

Outcome Measures

Primary Outcome Measures

1. Event-free Survival (EFS) [EFS assessed for up to 5 years, 2 year EFS reported]

   EFS is calculated for all patients from the date of initial registration on study until the first of the following: death from any cause, relapse from remission (CR or CRi) or completion of protocol Induction/Re-Induction therapy without documentation of CR or CRi. 2-year EFS by arm will be estimated using the Kaplan-Meier method. EFS will be compared between Arm I and Arm III and between Arm II and Arm III using Cox proportional hazards regression.

2. Rate of Allogeneic HCT [Up to 5 years]

   The goal of the transplant objective is to determine whether it is possible to conduct allogeneic HCT on 60% or more of adults with high-risk AML in first complete remission (alternative). If 40% or fewer of high-risk patients in CR can be transplanted, the proposed transplant support system will not be considered feasible. A one-sided binomial test compared to the null transplant rate will be conducted.

Secondary Outcome Measures

1. Disease-free Survival (DFS) Among High Risk Patients [DFS assessed for up to 5 years, 2 year DFS reported]

   DFS is calculated for patients who have achieved a CR or CRi (complete response with incomplete blood count recovery). DFS will be measured from the date of CR or CRi until relapse from CR or CRi for death from any cause. Observation is censored at the date of last follow-up for patients last known to be alive without report of relapse. 2-year DFS for high risk patients will be estimated using the Kaplan-Meier method.

2. EFS of Arm I Compared to Arm II [EFS assessed for up to 5 years, 2 year EFS reported]

   EFS is calculated for all patients from the date of initial registration on study until the first of the following: death from any cause, relapse from remission (CR or CRi) or completion of protocol Induction/Re-Induction therapy without documentation of CR or CRi. A two-sided test of the hazard ratio (HR) of 7:3: IA (versus the null hypothesis of HR =1) will be done using a proportional hazards regression model with the stratification factors included as covariates. 2-year EFS by arm will be estimated using the Kaplan-Meier method.

3. Frequency and Severity of Toxicities [Up to 5 years]

   Number of patients with Grade 3-5 adverse events that were possibly, probably or definitely related to study drug are reported by given type of adverse event.

Other Outcome Measures

1. Prevalence of the Mutation NPM1 in Patients on This Study. [Baseline]

   To estimate the prevalence of the mutation NPM1 in this patient population.

2. Prevalence of the Mutations IDH1, IDH2, TET2, DMT3A in Patients on This Study [Baseline]

   To estimate the prevalence of these mutations in this patient population. This objective will be analyzed as funding allows.

3. Cytogenetic Risk Distribution of Patients on This Study [Baseline]

   To estimate the cytogenetic risk distribution of patients on this study.

4. Overall Survival (OS) [OS assessed for up to 5 years, 2 year OS reported]

   To compare OS between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. OS is calculated for all patients from date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. 2-year OS by arm will be estimated using the Kaplan-Meier method.

5. Complete Response (CR) Rate [Up to 5 years]

   To compare the complete response rate between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. Complete response is defined as: ANC >= 1,000/mcl, platelet count >= 100,000/mcl, < 5% bone marrow blasts, no Auer rods, no evidence of extramedullary disease (no requirements for marrow cellularity or hemoglobin concentration)

6. Disease-free Survival (DFS) [DFS assessed for up to 5 years, 2 year DFS reported]

   To compare the disease-free survival (DFS) between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. DFS is calculated for patients who have achieved a CR or CRi (complete response with incomplete blood count recovery) . DFS will be measured from the date of CR or CRi until relapse from CR or CRi for death from any cause. Observation is censored at the date of last follow-up for patients last known to be alive without report of relapse. 2-year DFS by arm will be estimated using the Kaplan-Meier method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• STEP 1 - INDUCTION/RE-INDUCTION

• Patients must have morphologically confirmed newly diagnosed acute myelogenous leukemia (AML) with blood or bone marrow disease; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible; 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 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; prior all-trans retinoic acid (ATRA) for suspected APL is allowed; prior methotrexate for central nervous system (CNS) involvement is allowed; 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 corrected QT (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/mL within 28 days prior to registration

• Patients must be able to take oral medications

• Patients must have a history and physical examination obtained within 28 days prior to registration

• Patients must not be pregnant or nursing; 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

• As part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

• 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 blood count 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	Anchorage Radiation Therapy Center	Anchorage	Alaska	United States	99504
3	Alaska Breast Care and Surgery LLC	Anchorage	Alaska	United States	99508
4	Alaska Oncology and Hematology LLC	Anchorage	Alaska	United States	99508
5	Alaska Regional Hospital	Anchorage	Alaska	United States	99508
6	Alaska Women's Cancer Care	Anchorage	Alaska	United States	99508
7	Anchorage Oncology Centre	Anchorage	Alaska	United States	99508
8	Katmai Oncology Group	Anchorage	Alaska	United States	99508
9	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
10	University of Arizona Cancer Center-Orange Grove Campus	Tucson	Arizona	United States	85704
11	University of Arizona Cancer Center-North Campus	Tucson	Arizona	United States	85719
12	The University of Arizona Medical Center-University Campus	Tucson	Arizona	United States	85724
13	Yuma Cancer Center	Yuma	Arizona	United States	85364
14	Mercy Cancer Center-Hot Springs	Hot Springs	Arkansas	United States	71913
15	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
16	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
17	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
18	Fremont - Rideout Cancer Center	Marysville	California	United States	95901
19	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
20	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
21	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
22	Poudre Valley Hospital	Fort Collins	Colorado	United States	80524
23	Hartford Hospital	Hartford	Connecticut	United States	06102
24	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
25	Yale University	New Haven	Connecticut	United States	06520
26	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
27	Moffitt Cancer Center	Tampa	Florida	United States	33612
28	Northside Hospital	Atlanta	Georgia	United States	30342
29	Northside Hospital-Forsyth	Cumming	Georgia	United States	30041
30	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
31	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
32	Kootenai Medical Center	Coeur d'Alene	Idaho	United States	83814
33	Saint Luke's Mountain States Tumor Institute - Fruitland	Fruitland	Idaho	United States	83619
34	Saint Luke's Mountain States Tumor Institute - Meridian	Meridian	Idaho	United States	83642
35	Saint Luke's Mountain States Tumor Institute - Nampa	Nampa	Idaho	United States	83686
36	Kootenai Cancer Center	Post Falls	Idaho	United States	83854
37	Kootenai Cancer Clinic	Sandpoint	Idaho	United States	83864
38	Saint Luke's Mountain States Tumor Institute-Twin Falls	Twin Falls	Idaho	United States	83301
39	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
40	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
41	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
42	Memorial Hospital of Carbondale	Carbondale	Illinois	United States	62902
43	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
44	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
45	Mount Sinai Hospital Medical Center	Chicago	Illinois	United States	60608
46	Northwestern University	Chicago	Illinois	United States	60611
47	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
48	Cancer Care Center of Decatur	Decatur	Illinois	United States	62526
49	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
50	Crossroads Cancer Center	Effingham	Illinois	United States	62401
51	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
52	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
53	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
54	Western Illinois Cancer Treatment Center	Galesburg	Illinois	United States	61401
55	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois	United States	60026
56	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois	United States	60035
57	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois	United States	60035
58	Presence Saint Mary's Hospital	Kankakee	Illinois	United States	60901
59	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
60	NorthShore Hematology Oncology-Libertyville	Libertyville	Illinois	United States	60048
61	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
62	Loyola University Medical Center	Maywood	Illinois	United States	60153
63	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
64	Illinois Cancer Specialists-Niles	Niles	Illinois	United States	60714
65	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
66	Radiation Oncology of Northern Illinois	Ottawa	Illinois	United States	61350
67	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
68	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
69	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61603
70	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
71	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois	United States	61615
72	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
73	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
74	Valley Radiation Oncology	Peru	Illinois	United States	61354
75	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
76	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois	United States	61114
77	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois	United States	60076
78	North Shore Medical Center	Skokie	Illinois	United States	60076
79	Central Illinois Hematology Oncology Center	Springfield	Illinois	United States	62702
80	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
81	Springfield Clinic	Springfield	Illinois	United States	62702
82	Memorial Medical Center	Springfield	Illinois	United States	62781
83	Cancer Care Specialists of Illinois-Swansea	Swansea	Illinois	United States	62226
84	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
85	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
86	IU Health Central Indiana Cancer Centers-East	Indianapolis	Indiana	United States	46219
87	Franciscan Health Indianapolis	Indianapolis	Indiana	United States	46237
88	Reid Health	Richmond	Indiana	United States	47374
89	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa	United States	50010
90	McFarland Clinic PC-Boone	Boone	Iowa	United States	50036
91	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
92	Mercy Cancer Center-West Lakes	Clive	Iowa	United States	50325
93	Alegent Health Mercy Hospital	Council Bluffs	Iowa	United States	51503
94	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
95	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
96	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
97	McFarland Clinic PC-Jefferson	Jefferson	Iowa	United States	50129
98	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa	United States	50158
99	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
100	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51104
101	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
102	Mercy Medical Center-West Lakes	West Des Moines	Iowa	United States	50266
103	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
104	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
105	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
106	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
107	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
108	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
109	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
110	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
111	Cancer Center of Kansas-Liberal	Liberal	Kansas	United States	67905
112	Cancer Center of Kansas-Manhattan	Manhattan	Kansas	United States	66502
113	Cancer Center of Kansas - McPherson	McPherson	Kansas	United States	67460
114	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
115	Menorah Medical Center	Overland Park	Kansas	United States	66209
116	Saint Luke's South Hospital	Overland Park	Kansas	United States	66213
117	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
118	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
119	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
120	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
121	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
122	Associates In Womens Health	Wichita	Kansas	United States	67208
123	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
124	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
125	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
126	Wesley Medical Center	Wichita	Kansas	United States	67214
127	Wichita NCI Community Oncology Research Program	Wichita	Kansas	United States	67214
128	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
129	Flaget Memorial Hospital	Bardstown	Kentucky	United States	40004
130	Commonwealth Cancer Center-Corbin	Corbin	Kentucky	United States	40701
131	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky	United States	41017
132	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky	United States	40504
133	Saint Joseph Hospital East	Lexington	Kentucky	United States	40509
134	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
135	Jewish Hospital	Louisville	Kentucky	United States	40202
136	Saints Mary and Elizabeth Hospital	Louisville	Kentucky	United States	40215
137	Jewish Hospital Medical Center Northeast	Louisville	Kentucky	United States	40245
138	Jewish Hospital Medical Center South	Shepherdsville	Kentucky	United States	40165
139	Baton Rouge General Medical Center	Baton Rouge	Louisiana	United States	70806
140	Hematology/Oncology Clinic LLP	Baton Rouge	Louisiana	United States	70809
141	West Jefferson Medical Center	Marrero	Louisiana	United States	70072
142	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
143	Harold Alfond Center for Cancer Care	Augusta	Maine	United States	04330
144	Eastern Maine Medical Center	Bangor	Maine	United States	04401
145	Lafayette Family Cancer Center-EMMC	Brewer	Maine	United States	04412
146	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
147	Tufts Medical Center	Boston	Massachusetts	United States	02111
148	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
149	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
150	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
151	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
152	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
153	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
154	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
155	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan	United States	49307
156	Beaumont Hospital-Dearborn	Dearborn	Michigan	United States	48124
157	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
158	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
159	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
160	Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
161	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
162	Hurley Medical Center	Flint	Michigan	United States	48503
163	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
164	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
165	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
166	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
167	Allegiance Health	Jackson	Michigan	United States	49201
168	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
169	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
170	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
171	Sparrow Hospital	Lansing	Michigan	United States	48912
172	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
173	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
174	Assarian Cancer Center	Novi	Michigan	United States	48374-1236
175	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
176	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
177	Spectrum Health Reed City Hospital	Reed City	Michigan	United States	49677
178	Saint Mary's of Michigan	Saginaw	Michigan	United States	48601
179	Providence Hospital-Southfield Cancer Center	Southfield	Michigan	United States	48075
180	Munson Medical Center	Traverse City	Michigan	United States	49684
181	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
182	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
183	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
184	Fairview-Southdale Hospital	Edina	Minnesota	United States	55435
185	Unity Hospital	Fridley	Minnesota	United States	55432
186	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
187	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
188	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
189	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
190	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
191	Health Partners Inc	Minneapolis	Minnesota	United States	55454
192	New Ulm Medical Center	New Ulm	Minnesota	United States	56073
193	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
194	Mayo Clinic	Rochester	Minnesota	United States	55905
195	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
196	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
197	Regions Hospital	Saint Paul	Minnesota	United States	55101
198	United Hospital	Saint Paul	Minnesota	United States	55102
199	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
200	Lakeview Hospital	Stillwater	Minnesota	United States	55082
201	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
202	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
203	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
204	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
205	Central Care Cancer Center-Carrie J Babb Cancer Center	Bolivar	Missouri	United States	65613
206	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri	United States	63628
207	CoxHealth Cancer Center	Branson	Missouri	United States	65616
208	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
209	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
210	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
211	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri	United States	63141
212	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
213	Capital Region Medical Center-Goldschmidt Cancer Center	Jefferson City	Missouri	United States	65109
214	Freeman Health System	Joplin	Missouri	United States	64804
215	Mercy Hospital-Joplin	Joplin	Missouri	United States	64804
216	Saint Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
217	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri	United States	64118
218	Research Medical Center	Kansas City	Missouri	United States	64132
219	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
220	Liberty Radiation Oncology Center	Liberty	Missouri	United States	64068
221	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri	United States	65401
222	Saint John's Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
223	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
224	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
225	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
226	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
227	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
228	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri	United States	63670
229	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
230	CoxHealth South Hospital	Springfield	Missouri	United States	65807
231	Missouri Baptist Sullivan Hospital	Sullivan	Missouri	United States	63080
232	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri	United States	63127
233	Billings Clinic Cancer Center	Billings	Montana	United States	59101
234	Saint Vincent Healthcare	Billings	Montana	United States	59101
235	Montana Cancer Consortium NCORP	Billings	Montana	United States	59102
236	Saint Vincent Frontier Cancer Center	Billings	Montana	United States	59102
237	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
238	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
239	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
240	Great Falls Clinic	Great Falls	Montana	United States	59405
241	Saint Peter's Community Hospital	Helena	Montana	United States	59601
242	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
243	Montana Cancer Specialists	Missoula	Montana	United States	59802
244	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
245	Community Medical Hospital	Missoula	Montana	United States	59804
246	CHI Health Saint Francis	Grand Island	Nebraska	United States	68803
247	Heartland Hematology and Oncology	Kearney	Nebraska	United States	68845
248	CHI Health Good Samaritan	Kearney	Nebraska	United States	68847
249	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska	United States	68510
250	Alegent Health Immanuel Medical Center	Omaha	Nebraska	United States	68122
251	Hemotology and Oncology Consultants PC	Omaha	Nebraska	United States	68122
252	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
253	Alegent Health Lakeside Hospital	Omaha	Nebraska	United States	68130
254	Creighton University Medical Center	Omaha	Nebraska	United States	68131
255	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
256	Midlands Community Hospital	Papillion	Nebraska	United States	68046
257	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
258	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
259	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
260	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
261	North Shore University Hospital	Manhasset	New York	United States	11030
262	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
263	Northwell Health/Center for Advanced Medicine	New Hyde Park	New York	United States	11040
264	Mount Sinai Hospital	New York	New York	United States	10029
265	University of Rochester	Rochester	New York	United States	14642
266	Cancer Care of Western North Carolina	Asheville	North Carolina	United States	28801
267	Mission Hospital-Memorial Campus	Asheville	North Carolina	United States	28801
268	Mountain Radiation Oncology	Asheville	North Carolina	United States	28801
269	Asheville Hematology-Oncology Associates	Asheville	North Carolina	United States	28803
270	Hope Women's Cancer Centers-Asheville	Asheville	North Carolina	United States	28816
271	Transylvania Regional Hospital	Brevard	North Carolina	United States	28712
272	Duke University Medical Center	Durham	North Carolina	United States	27710
273	Angel Medical Center	Franklin	North Carolina	United States	28734
274	Park Ridge Hospital Breast Health Center	Hendersonville	North Carolina	United States	28792
275	Kinston Medical Specialists PA	Kinston	North Carolina	United States	28501
276	McDowell Hospital	Marion	North Carolina	United States	28752
277	Blue Ridge Regional Hospital	Spruce Pine	North Carolina	United States	28777
278	Southeast Clinical Oncology Research (SCOR) Consortium NCORP	Winston-Salem	North Carolina	United States	27104
279	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
280	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
281	Summa Barberton Hospital	Barberton	Ohio	United States	44203
282	Miami Valley Hospital South	Centerville	Ohio	United States	45459
283	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio	United States	45202
284	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio	United States	45211
285	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio	United States	45220
286	Oncology Hematology Care Inc - Anderson	Cincinnati	Ohio	United States	45230
287	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio	United States	45236
288	The Jewish Hospital	Cincinnati	Ohio	United States	45236
289	Bethesda North Hospital	Cincinnati	Ohio	United States	45242
290	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio	United States	45242
291	TriHealth Cancer Institute-Westside	Cincinnati	Ohio	United States	45247
292	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio	United States	45255
293	Case Western Reserve University	Cleveland	Ohio	United States	44106
294	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
295	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
296	Grandview Hospital	Dayton	Ohio	United States	45405
297	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
298	Miami Valley Hospital	Dayton	Ohio	United States	45409
299	Samaritan North Health Center	Dayton	Ohio	United States	45415
300	Dayton NCI Community Oncology Research Program	Dayton	Ohio	United States	45420
301	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio	United States	45014
302	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
303	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
304	Wayne Hospital	Greenville	Ohio	United States	45331
305	Kettering Medical Center	Kettering	Ohio	United States	45429
306	Springfield Regional Cancer Center	Springfield	Ohio	United States	45504
307	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
308	Upper Valley Medical Center	Troy	Ohio	United States	45373
309	Wright-Patterson Medical Center	Wright-Patterson Air Force Base	Ohio	United States	45433-5529
310	Greene Memorial Hospital	Xenia	Ohio	United States	45385
311	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
312	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
313	Warren Clinic Oncology-Tulsa	Tulsa	Oklahoma	United States	74146
314	Saint Charles Health System	Bend	Oregon	United States	97701
315	Clackamas Radiation Oncology Center	Clackamas	Oregon	United States	97015
316	Providence Oncology and Hematology Care Southeast	Clackamas	Oregon	United States	97015
317	Bay Area Hospital	Coos Bay	Oregon	United States	97420
318	Providence Milwaukie Hospital	Milwaukie	Oregon	United States	97222
319	Providence Newberg Medical Center	Newberg	Oregon	United States	97132
320	Providence Willamette Falls Medical Center	Oregon City	Oregon	United States	97045
321	Providence Portland Medical Center	Portland	Oregon	United States	97213
322	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
323	Oregon Health and Science University	Portland	Oregon	United States	97239
324	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
325	Ephrata Cancer Center	Ephrata	Pennsylvania	United States	17522
326	Ephrata Community Hospital	Ephrata	Pennsylvania	United States	17522
327	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
328	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
329	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
330	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
331	Drexel University School of Medicine	Philadelphia	Pennsylvania	United States	19102
332	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
333	WellSpan Health-York Cancer Center	York	Pennsylvania	United States	17403
334	WellSpan Health-York Hospital	York	Pennsylvania	United States	17403
335	AnMed Health Cancer Center	Anderson	South Carolina	United States	29621
336	Medical University of South Carolina	Charleston	South Carolina	United States	29425
337	Saint Francis Hospital	Greenville	South Carolina	United States	29601
338	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
339	Carolina Blood and Cancer Care Associates PA-Lancaster	Lancaster	South Carolina	United States	29720
340	Carolina Blood and Cancer Care Associates PA	Rock Hill	South Carolina	United States	29732
341	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
342	MGC Hematology Oncology-Union	Union	South Carolina	United States	29379
343	Memorial Hospital	Chattanooga	Tennessee	United States	37404
344	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee	United States	37067
345	Pulmonary Medicine Center of Chattanooga-Hixson	Hixson	Tennessee	United States	37343
346	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee	United States	37204
347	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
348	Memorial GYN Plus	Ooltewah	Tennessee	United States	37363
349	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
350	Ben Taub General Hospital	Houston	Texas	United States	77030
351	M D Anderson Cancer Center	Houston	Texas	United States	77030
352	Michael E DeBakey VA Medical Center	Houston	Texas	United States	77030
353	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah	United States	84003
354	Sandra L Maxwell Cancer Center	Cedar City	Utah	United States	84720
355	Logan Regional Hospital	Logan	Utah	United States	84321
356	Intermountain Medical Center	Murray	Utah	United States	84107
357	McKay-Dee Hospital Center	Ogden	Utah	United States	84403
358	Utah Valley Regional Medical Center	Provo	Utah	United States	84604
359	Dixie Medical Center Regional Cancer Center	Saint George	Utah	United States	84770
360	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah	United States	84106
361	LDS Hospital	Salt Lake City	Utah	United States	84143
362	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
363	University of Vermont College of Medicine	Burlington	Vermont	United States	05405
364	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
365	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington	United States	98520
366	Cancer Care Center at Island Hospital	Anacortes	Washington	United States	98221
367	Swedish Cancer Institute-Eastside Oncology Hematology	Bellevue	Washington	United States	98005
368	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington	United States	98225
369	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
370	Harrison Medical Center	Bremerton	Washington	United States	98310
371	Highline Medical Center-Main Campus	Burien	Washington	United States	98166
372	Providence Regional Cancer System-Centralia	Centralia	Washington	United States	98531
373	Swedish Medical Center-Edmonds	Edmonds	Washington	United States	98026
374	Saint Elizabeth Hospital	Enumclaw	Washington	United States	98022
375	Providence Regional Cancer Partnership	Everett	Washington	United States	98201
376	Saint Francis Hospital	Federal Way	Washington	United States	98003
377	Swedish Cancer Institute-Issaquah	Issaquah	Washington	United States	98029
378	Kadlec Clinic Hematology and Oncology	Kennewick	Washington	United States	99336
379	Seattle Cancer Care Alliance at EvergreenHealth	Kirkland	Washington	United States	98034
380	Providence Regional Cancer System-Lacey	Lacey	Washington	United States	98503
381	Saint Clare Hospital	Lakewood	Washington	United States	98499
382	PeaceHealth Saint John Medical Center	Longview	Washington	United States	98632
383	Skagit Valley Hospital	Mount Vernon	Washington	United States	98274
384	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington	United States	98370
385	Harborview Medical Center	Seattle	Washington	United States	98104
386	Minor and James Medical PLLC	Seattle	Washington	United States	98104
387	Pacific Gynecology Specialists	Seattle	Washington	United States	98104
388	Swedish Medical Center-Ballard Campus	Seattle	Washington	United States	98107
389	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
390	Kaiser Permanente Washington	Seattle	Washington	United States	98112
391	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
392	University of Washington Medical Center	Seattle	Washington	United States	98195
393	United General Hospital	Sedro-Woolley	Washington	United States	98284
394	Providence Regional Cancer System-Shelton	Shelton	Washington	United States	98584
395	Rockwood Clinic Cancer Treatment Center-Valley	Spokane Valley	Washington	United States	99216
396	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
397	Rockwood Cancer Treatment Center-DHEC-Downtown	Spokane	Washington	United States	99204
398	Evergreen Hematology and Oncology PS	Spokane	Washington	United States	99218
399	Rockwood Clinic	Spokane	Washington	United States	99220
400	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington	United States	98405
401	Northwest Medical Specialties PLLC	Tacoma	Washington	United States	98405
402	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
403	Compass Oncology Vancouver	Vancouver	Washington	United States	98684
404	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
405	Wenatchee Valley Hospital and Clinics	Wenatchee	Washington	United States	98801
406	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
407	Providence Regional Cancer System-Yelm	Yelm	Washington	United States	98597
408	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
409	Sacred Heart Hospital	Eau Claire	Wisconsin	United States	54701
410	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
411	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
412	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
413	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
414	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin	United States	53038
415	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
416	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
417	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
418	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
419	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
420	Marshfield Medical Center	Marshfield	Wisconsin	United States	54449
421	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
422	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin	United States	54548
423	ProHealth D N Greenwald Center	Mukwonago	Wisconsin	United States	53149
424	Cancer Center of Western Wisconsin	New Richmond	Wisconsin	United States	54017
425	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
426	Green Bay Oncology - Oconto Falls	Oconto Falls	Wisconsin	United States	54154
427	Marshfield Clinic at James Beck Cancer Center	Rhinelander	Wisconsin	United States	54501
428	Marshfield Clinic-Rice Lake Center	Rice Lake	Wisconsin	United States	54868
429	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
430	Marshfield Clinic Cancer Care at Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
431	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
432	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
433	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin	United States	53188
434	Marshfield Clinic-Wausau Center	Wausau	Wisconsin	United States	54401
435	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
436	Saint Clare's Hospital	Weston	Wisconsin	United States	54476
437	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
438	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
439	Big Horn Basin Cancer Center	Cody	Wyoming	United States	82414
440	Billings Clinic-Cody	Cody	Wyoming	United States	82414
441	Welch Cancer Center	Sheridan	Wyoming	United States	82801
442	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
443	The Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
444	Atlantic Health Sciences Corporation-Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
445	QEII Health Sciences Centre/Nova Scotia Health Authority	Halifax	Nova Scotia	Canada	B3H 2Y9
446	CIUSSSEMTL-Hopital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T 2M4
447	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Guillermo Garcia-Manero, Southwest Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 2, 2015

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01802333
• Other Study ID Numbers: NCI-2013-00490; NCI-2013-00490; S1203; PS1203_A06PAMDREVW01; SWOG-S1203; S1203; S1203; U10CA180888; U10CA032102
• First Posted: Mar 1, 2013
• Last Update Posted: Dec 19, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Daunorubicin; Vorinostat; Idarubicin

Study Results

Participant Flow

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Period Title: Overall Study
STARTED	263	267	224
High Risk Patients	60	61	38
High Risk Patients Achieved CR/CRi	38	40	29
Known NPM1 Status at Baseline	169	156	142
Known Cytogenetic Risk at Baseline	252	250	210
COMPLETED	214	206	161
NOT COMPLETED	49	61	63

Baseline Characteristics

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)	Total
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO	Total of all reporting groups
Overall Participants	261	261	216	738
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48.3	51.5	48.9	49.8
Age, Customized (Count of Participants)
< 40 years	68 26.1%	65 24.9%	55 25.5%	188 25.5%
>= 40 years	193 73.9%	196 75.1%	161 74.5%	550 74.5%
Sex: Female, Male (Count of Participants)
Female	131 50.2%	127 48.7%	102 47.2%	360 48.8%
Male	130 49.8%	134 51.3%	114 52.8%	378 51.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	19 7.3%	22 8.4%	21 9.7%	62 8.4%
Not Hispanic or Latino	226 86.6%	217 83.1%	185 85.6%	628 85.1%
Unknown or Not Reported	16 6.1%	22 8.4%	10 4.6%	48 6.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.1%	0 0%	3 1.4%	6 0.8%
Asian	6 2.3%	4 1.5%	7 3.2%	17 2.3%
Native Hawaiian or Other Pacific Islander	2 0.8%	1 0.4%	0 0%	3 0.4%
Black or African American	19 7.3%	19 7.3%	17 7.9%	55 7.5%
White	218 83.5%	217 83.1%	178 82.4%	613 83.1%
More than one race	1 0.4%	1 0.4%	0 0%	2 0.3%
Unknown or Not Reported	12 4.6%	19 7.3%	11 5.1%	42 5.7%
Onset of Leukemia (Count of Participants)
De novo	236 90.4%	236 90.4%	193 89.4%	665 90.1%
Tx. related/arose from antecededent hem. disease	25 9.6%	25 9.6%	23 10.6%	73 9.9%

Outcome Measures

1. Primary Outcome

Title	Event-free Survival (EFS)
Description	EFS is calculated for all patients from the date of initial registration on study until the first of the following: death from any cause, relapse from remission (CR or CRi) or completion of protocol Induction/Re-Induction therapy without documentation of CR or CRi. 2-year EFS by arm will be estimated using the Kaplan-Meier method. EFS will be compared between Arm I and Arm III and between Arm II and Arm III using Cox proportional hazards regression.
Time Frame	EFS assessed for up to 5 years, 2 year EFS reported

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	261	261	216
Number (95% Confidence Interval) [Proportion of participants]	0.36 0.1%	0.41 0.2%	0.37 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride), Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
	Comments	Arm I was compared with Arm III using a two-sided test of the null hypothesis (HR=1) at the 0.045 level.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Regression, Cox
	Comments	Adjusted for: Age (< 40 vs. >= 40) and Onset of AML (de novo vs. treatment related and/or AML arising from antecedent hematologic disease)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm II (High-dose Cytarabine, Idarubicin), Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
	Comments	Arm II was compared with Arm III using a two-sided test of the null hypothesis (HR=1) at the 0.045 level.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Regression, Cox
	Comments	Adjusted for: Age (< 40 vs. >= 40) and Onset of AML (de novo vs. treatment related and/or AML arising from antecedent hematologic disease)

2. Primary Outcome

Title	Rate of Allogeneic HCT
Description	The goal of the transplant objective is to determine whether it is possible to conduct allogeneic HCT on 60% or more of adults with high-risk AML in first complete remission (alternative). If 40% or fewer of high-risk patients in CR can be transplanted, the proposed transplant support system will not be considered feasible. A one-sided binomial test compared to the null transplant rate will be conducted.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Eligible patients with high-risk AML who achieved CR or CRi, regardless of treatment arm.

Arm/Group Title	High Risk Patients in First Complete Remission
Arm/Group Description	This group includes patients from any of the three treatment arms who have high-risk AML (by cytogenetics) and who achieved a complete remission (CR) or complete remission with incomplete blood count recovery (CRi).
Measure Participants	107
Number (95% Confidence Interval) [percentage of patients]	65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Exact binomial test, 1-sided
	Comments

3. Secondary Outcome

Title	Disease-free Survival (DFS) Among High Risk Patients
Description	DFS is calculated for patients who have achieved a CR or CRi (complete response with incomplete blood count recovery). DFS will be measured from the date of CR or CRi until relapse from CR or CRi for death from any cause. Observation is censored at the date of last follow-up for patients last known to be alive without report of relapse. 2-year DFS for high risk patients will be estimated using the Kaplan-Meier method.
Time Frame	DFS assessed for up to 5 years, 2 year DFS reported

Outcome Measure Data

Analysis Population Description

Eligible, high risk patients, regardless of treatment arm.

Arm/Group Title	High Risk Patients
Arm/Group Description	This group includes patients from any of the three treatment arms who have high-risk AML (by cytogenetics).
Measure Participants	159
Number (95% Confidence Interval) [Proportion of participants]	0.30 0.1%

4. Secondary Outcome

Title	EFS of Arm I Compared to Arm II
Description	EFS is calculated for all patients from the date of initial registration on study until the first of the following: death from any cause, relapse from remission (CR or CRi) or completion of protocol Induction/Re-Induction therapy without documentation of CR or CRi. A two-sided test of the hazard ratio (HR) of 7:3: IA (versus the null hypothesis of HR =1) will be done using a proportional hazards regression model with the stratification factors included as covariates. 2-year EFS by arm will be estimated using the Kaplan-Meier method.
Time Frame	EFS assessed for up to 5 years, 2 year EFS reported

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies
Measure Participants	261	261
Number (95% Confidence Interval) [Proportion of participants]	0.36 0.1%	0.41 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride), Arm II (High-dose Cytarabine, Idarubicin)
	Comments	Arm I was compared with Arm II using a two-sided test of the null hypothesis (HR=1).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Regression, Cox
	Comments	Adjusted for: Age (< 40 vs. >= 40) and Onset of AML (de novo vs. treatment related and/or AML arising from antecedent hematologic disease)

5. Secondary Outcome

Title	Frequency and Severity of Toxicities
Description	Number of patients with Grade 3-5 adverse events that were possibly, probably or definitely related to study drug are reported by given type of adverse event.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Eligible patients who started treatment

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.	INDUCTION/RE-INDUCTION: 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.	INDUCTION/RE-INDUCTION: Patients receive vorinostat PO 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.
Measure Participants	261	259	211
Abdominal distension	1 0.4%	0 0%	1 0.5%
Abdominal infection	1 0.4%	1 0.4%	1 0.5%
Abdominal pain	4 1.5%	6 2.3%	9 4.2%
Acidosis	1 0.4%	1 0.4%	2 0.9%
Acute kidney injury	2 0.8%	5 1.9%	4 1.9%
Adult respiratory distress syndrome	1 0.4%	3 1.1%	4 1.9%
Alanine aminotransferase increased	12 4.6%	17 6.5%	20 9.3%
Alkaline phosphatase increased	2 0.8%	2 0.8%	1 0.5%
Alkalosis	1 0.4%	1 0.4%	2 0.9%
Allergic reaction	0 0%	0 0%	2 0.9%
Anal hemorrhage	0 0%	0 0%	1 0.5%
Anal pain	0 0%	1 0.4%	0 0%
Anal ulcer	0 0%	0 0%	1 0.5%
Anemia	158 60.5%	164 62.8%	106 49.1%
Anorectal infection	0 0%	0 0%	4 1.9%
Anorexia	5 1.9%	16 6.1%	12 5.6%
Aspartate aminotransferase increased	8 3.1%	15 5.7%	12 5.6%
Atelectasis	0 0%	0 0%	1 0.5%
Atrial fibrillation	0 0%	3 1.1%	1 0.5%
Atrial flutter	0 0%	1 0.4%	1 0.5%
Atrioventricular block complete	0 0%	1 0.4%	0 0%
Blood and lymphatic system disorders - Other	1 0.4%	1 0.4%	0 0%
Blood bilirubin increased	9 3.4%	15 5.7%	22 10.2%
Bone infection	1 0.4%	0 0%	0 0%
Bone pain	0 0%	1 0.4%	0 0%
Bronchopulmonary hemorrhage	1 0.4%	1 0.4%	3 1.4%
Bullous dermatitis	0 0%	2 0.8%	0 0%
CD4 lymphocytes decreased	1 0.4%	1 0.4%	0 0%
Cardiac arrest	1 0.4%	3 1.1%	2 0.9%
Cardiac disorders - Other, specify	1 0.4%	1 0.4%	1 0.5%
Cardiac troponin I increased	0 0%	1 0.4%	0 0%
Catheter related infection	3 1.1%	7 2.7%	4 1.9%
Chills	1 0.4%	0 0%	0 0%
Chronic kidney disease	0 0%	2 0.8%	0 0%
Cognitive disturbance	0 0%	0 0%	1 0.5%
Colitis	3 1.1%	9 3.4%	5 2.3%
Colonic hemorrhage	2 0.8%	0 0%	1 0.5%
Colonic perforation	0 0%	0 0%	1 0.5%
Conduction disorder	1 0.4%	0 0%	0 0%
Confusion	0 0%	2 0.8%	0 0%
Conjunctivitis	1 0.4%	0 0%	0 0%
Constipation	0 0%	1 0.4%	0 0%
Constrictive pericarditis	1 0.4%	0 0%	0 0%
Creatinine increased	1 0.4%	6 2.3%	4 1.9%
Death NOS	1 0.4%	1 0.4%	0 0%
Dehydration	1 0.4%	0 0%	3 1.4%
Dental caries	1 0.4%	0 0%	0 0%
Device related infection	1 0.4%	3 1.1%	0 0%
Diarrhea	15 5.7%	20 7.7%	38 17.6%
Disseminated intravascular coagulation	2 0.8%	1 0.4%	1 0.5%
Dry mouth	0 0%	1 0.4%	0 0%
Dry skin	0 0%	2 0.8%	0 0%
Duodenal hemorrhage	1 0.4%	0 0%	0 0%
Dyspepsia	1 0.4%	0 0%	0 0%
Dysphagia	1 0.4%	1 0.4%	0 0%
Dyspnea	3 1.1%	7 2.7%	8 3.7%
Edema cerebral	0 0%	0 0%	1 0.5%
Edema limbs	0 0%	3 1.1%	2 0.9%
Ejection fraction decreased	2 0.8%	6 2.3%	4 1.9%
Electrocardiogram QT corrected interval prolonged	0 0%	2 0.8%	2 0.9%
Encephalopathy	0 0%	1 0.4%	0 0%
Enterocolitis	1 0.4%	6 2.3%	5 2.3%
Enterocolitis infectious	1 0.4%	4 1.5%	4 1.9%
Epistaxis	2 0.8%	1 0.4%	2 0.9%
Erythema multiforme	1 0.4%	0 0%	0 0%
Erythroderma	0 0%	0 0%	1 0.5%
Esophageal hemorrhage	0 0%	0 0%	1 0.5%
Esophageal pain	1 0.4%	1 0.4%	0 0%
Esophagitis	3 1.1%	2 0.8%	1 0.5%
Eye infection	0 0%	1 0.4%	0 0%
Fatigue	14 5.4%	18 6.9%	13 6%
Febrile neutropenia	152 58.2%	160 61.3%	114 52.8%
Fever	4 1.5%	7 2.7%	6 2.8%
GGT increased	3 1.1%	2 0.8%	4 1.9%
Gait disturbance	0 0%	0 0%	1 0.5%
Gastric hemorrhage	0 0%	2 0.8%	3 1.4%
Gastritis	1 0.4%	0 0%	0 0%
Gastroesophageal reflux disease	1 0.4%	0 0%	0 0%
Gastrointestinal disorders - Other, specify	1 0.4%	5 1.9%	1 0.5%
General disorders and admin site conditions-Other	0 0%	4 1.5%	1 0.5%
Generalized muscle weakness	2 0.8%	1 0.4%	2 0.9%
Genital edema	0 0%	0 0%	1 0.5%
Glucose intolerance	1 0.4%	0 0%	0 0%
Gum infection	1 0.4%	0 0%	0 0%
Headache	2 0.8%	2 0.8%	4 1.9%
Heart failure	3 1.1%	2 0.8%	3 1.4%
Hematoma	0 0%	1 0.4%	0 0%
Hematuria	0 0%	2 0.8%	0 0%
Hepatic failure	1 0.4%	0 0%	0 0%
Hepatic infection	1 0.4%	1 0.4%	0 0%
Hepatobiliary disorders - Other, specify	1 0.4%	0 0%	1 0.5%
Hyperglycemia	5 1.9%	12 4.6%	16 7.4%
Hyperhidrosis	1 0.4%	1 0.4%	0 0%
Hyperkalemia	0 0%	1 0.4%	1 0.5%
Hypermagnesemia	0 0%	1 0.4%	0 0%
Hypernatremia	0 0%	0 0%	2 0.9%
Hypertension	7 2.7%	6 2.3%	6 2.8%
Hyperuricemia	0 0%	1 0.4%	1 0.5%
Hypoalbuminemia	5 1.9%	8 3.1%	8 3.7%
Hypocalcemia	8 3.1%	17 6.5%	25 11.6%
Hypoglycemia	0 0%	0 0%	1 0.5%
Hypokalemia	18 6.9%	20 7.7%	24 11.1%
Hypomagnesemia	0 0%	1 0.4%	2 0.9%
Hyponatremia	20 7.7%	20 7.7%	9 4.2%
Hypophosphatemia	21 8%	31 11.9%	31 14.4%
Hypotension	3 1.1%	12 4.6%	9 4.2%
Hypoxia	2 0.8%	4 1.5%	9 4.2%
Ileus	0 0%	1 0.4%	2 0.9%
Infections and infestations - Other, specify	18 6.9%	21 8%	14 6.5%
Infective myositis	1 0.4%	0 0%	0 0%
Injury, poison and procedural complications-Other	1 0.4%	0 0%	0 0%
Intracranial hemorrhage	0 0%	0 0%	1 0.5%
Investigations - Other, specify	1 0.4%	6 2.3%	3 1.4%
Irregular menstruation	1 0.4%	0 0%	0 0%
Jejunal obstruction	0 0%	0 0%	1 0.5%
Kidney infection	0 0%	1 0.4%	0 0%
Laryngeal edema	1 0.4%	0 0%	0 0%
Laryngeal mucositis	0 0%	0 0%	1 0.5%
Left ventricular systolic dysfunction	2 0.8%	3 1.1%	0 0%
Leukocytosis	1 0.4%	1 0.4%	1 0.5%
Lipase increased	0 0%	0 0%	2 0.9%
Lower gastrointestinal hemorrhage	0 0%	1 0.4%	3 1.4%
Lung infection	21 8%	22 8.4%	14 6.5%
Lymphocyte count decreased	89 34.1%	107 41%	77 35.6%
Menorrhagia	1 0.4%	0 0%	0 0%
Metabolism and nutrition disorders-Other, specify	1 0.4%	1 0.4%	0 0%
Middle ear inflammation	1 0.4%	0 0%	0 0%
Mucosal infection	1 0.4%	0 0%	1 0.5%
Mucositis oral	19 7.3%	18 6.9%	11 5.1%
Multi-organ failure	1 0.4%	3 1.1%	5 2.3%
Musculoskeletal and connective tiss disorder-Other	0 0%	1 0.4%	1 0.5%
Myalgia	0 0%	0 0%	1 0.5%
Nausea	7 2.7%	15 5.7%	5 2.3%
Neck edema	0 0%	0 0%	1 0.5%
Nervous system disorders - Other, specify	0 0%	1 0.4%	0 0%
Neutrophil count decreased	141 54%	128 49%	104 48.1%
Non-cardiac chest pain	1 0.4%	0 0%	1 0.5%
Oral pain	5 1.9%	5 1.9%	0 0%
Pain	1 0.4%	0 0%	0 0%
Pain in extremity	1 0.4%	0 0%	1 0.5%
Palmar-plantar erythrodysesthesia syndrome	0 0%	2 0.8%	1 0.5%
Papulopustular rash	0 0%	1 0.4%	0 0%
Paresthesia	0 0%	0 0%	1 0.5%
Pericardial effusion	0 0%	0 0%	1 0.5%
Pericardial tamponade	0 0%	0 0%	1 0.5%
Periorbital edema	0 0%	1 0.4%	0 0%
Peripheral sensory neuropathy	0 0%	0 0%	1 0.5%
Pharyngeal mucositis	1 0.4%	0 0%	0 0%
Pharyngitis	1 0.4%	0 0%	0 0%
Platelet count decreased	175 67%	168 64.4%	128 59.3%
Pleural effusion	1 0.4%	0 0%	1 0.5%
Pneumonitis	1 0.4%	4 1.5%	2 0.9%
Pruritus	0 0%	1 0.4%	1 0.5%
Pulmonary edema	1 0.4%	2 0.8%	5 2.3%
Purpura	0 0%	1 0.4%	0 0%
Rash acneiform	1 0.4%	1 0.4%	0 0%
Rash maculo-papular	11 4.2%	26 10%	10 4.6%
Rectal hemorrhage	1 0.4%	0 0%	0 0%
Rectal pain	1 0.4%	0 0%	1 0.5%
Renal and urinary disorders - Other, specify	0 0%	1 0.4%	0 0%
Resp, thoracic and mediastinal disorders - Other	1 0.4%	3 1.1%	2 0.9%
Respiratory failure	3 1.1%	8 3.1%	14 6.5%
Restrictive cardiomyopathy	1 0.4%	0 0%	0 0%
Salivary duct inflammation	1 0.4%	0 0%	0 0%
Scrotal infection	0 0%	0 0%	1 0.5%
Scrotal pain	0 0%	0 0%	1 0.5%
Seizure	1 0.4%	0 0%	1 0.5%
Sepsis	16 6.1%	26 10%	34 15.7%
Sinus bradycardia	0 0%	0 0%	1 0.5%
Sinus tachycardia	0 0%	2 0.8%	2 0.9%
Sinusitis	2 0.8%	0 0%	0 0%
Skin and subcutaneous tissue disorders - Other	0 0%	2 0.8%	1 0.5%
Skin infection	5 1.9%	1 0.4%	4 1.9%
Skin ulceration	0 0%	0 0%	1 0.5%
Small intestinal obstruction	1 0.4%	0 0%	0 0%
Soft tissue infection	1 0.4%	0 0%	0 0%
Sore throat	1 0.4%	2 0.8%	2 0.9%
Stomach pain	1 0.4%	0 0%	0 0%
Stroke	0 0%	1 0.4%	1 0.5%
Supraventricular tachycardia	0 0%	1 0.4%	1 0.5%
Syncope	2 0.8%	2 0.8%	3 1.4%
Testicular disorder	0 0%	1 0.4%	0 0%
Thromboembolic event	1 0.4%	0 0%	0 0%
Thrombotic thrombocytopenic purpura	3 1.1%	0 0%	1 0.5%
Tooth infection	1 0.4%	0 0%	0 0%
Tumor lysis syndrome	4 1.5%	8 3.1%	9 4.2%
Typhlitis	8 3.1%	14 5.4%	23 10.6%
Upper gastrointestinal hemorrhage	1 0.4%	0 0%	1 0.5%
Upper respiratory infection	2 0.8%	1 0.4%	2 0.9%
Urinary incontinence	0 0%	0 0%	1 0.5%
Urinary tract infection	5 1.9%	2 0.8%	6 2.8%
Urine output decreased	0 0%	0 0%	1 0.5%
Vaginal hemorrhage	0 0%	0 0%	2 0.9%
Vascular access complication	0 0%	2 0.8%	1 0.5%
Vasovagal reaction	0 0%	1 0.4%	1 0.5%
Ventricular tachycardia	0 0%	1 0.4%	0 0%
Vomiting	3 1.1%	6 2.3%	4 1.9%
Weight loss	2 0.8%	0 0%	2 0.9%
White blood cell decreased	156 59.8%	150 57.5%	112 51.9%
Wound infection	1 0.4%	0 0%	0 0%

6. Other Pre-specified Outcome

Title	Prevalence of the Mutation NPM1 in Patients on This Study.
Description	To estimate the prevalence of the mutation NPM1 in this patient population.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Eligible patients with known NPM1 status at baseline

Arm/Group Title	All Arms Combined
Arm/Group Description	This group includes all patients enrolled to the trial, regardless of treatment assignment.
Measure Participants	467
Number [percentage of patients]	33

7. Other Pre-specified Outcome

Title	Prevalence of the Mutations IDH1, IDH2, TET2, DMT3A in Patients on This Study
Description	To estimate the prevalence of these mutations in this patient population. This objective will be analyzed as funding allows.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

There was not sufficient funding to test patients for IDH1, IDH2, TET2, or DMT3A. Therefore, this objective was not completed.

Arm/Group Title	All Arms Combined
Arm/Group Description	This group includes all patients enrolled to the trial, regardless of treatment assignment.
Measure Participants	0

8. Other Pre-specified Outcome

Title	Cytogenetic Risk Distribution of Patients on This Study
Description	To estimate the cytogenetic risk distribution of patients on this study.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Eligible patients with known cytogenetic risk at baseline

Arm/Group Title	All Arms Combined
Arm/Group Description	This group includes all patients enrolled to the trial, regardless of treatment assignment.
Measure Participants	712
High risk	22.3 8.5%
Intermediate risk	64.2 24.6%
Low risk	13.5 5.2%

9. Other Pre-specified Outcome

Title	Overall Survival (OS)
Description	To compare OS between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. OS is calculated for all patients from date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. 2-year OS by arm will be estimated using the Kaplan-Meier method.
Time Frame	OS assessed for up to 5 years, 2 year OS reported

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	261	261	216
Number (95% Confidence Interval) [Proportion of participants]	0.56 0.2%	0.59 0.2%	0.58 0.3%

10. Other Pre-specified Outcome

Title	Complete Response (CR) Rate
Description	To compare the complete response rate between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. Complete response is defined as: ANC >= 1,000/mcl, platelet count >= 100,000/mcl, < 5% bone marrow blasts, no Auer rods, no evidence of extramedullary disease (no requirements for marrow cellularity or hemoglobin concentration)
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	261	261	216
Number (95% Confidence Interval) [Percentage of participants]	75 28.7%	80 30.7%	77 35.6%

11. Other Pre-specified Outcome

Title	Disease-free Survival (DFS)
Description	To compare the disease-free survival (DFS) between patients who receive standard 7+3 therapy or IA to patients who receive IA + vorinostat. DFS is calculated for patients who have achieved a CR or CRi (complete response with incomplete blood count recovery) . DFS will be measured from the date of CR or CRi until relapse from CR or CRi for death from any cause. Observation is censored at the date of last follow-up for patients last known to be alive without report of relapse. 2-year DFS by arm will be estimated using the Kaplan-Meier method.
Time Frame	DFS assessed for up to 5 years, 2 year DFS reported

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)	Arm II (High-dose Cytarabine, Idarubicin)	Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy. CONSOLIDATION: Patients receive cytarabine IV over 3 hours every 12 hours on days 1, 3, and 5. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Daunorubicin Hydrochloride: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTION: 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. CONSOLIDATION: Patients receive cytarabine IV continuously on days 1-3 and idarubicin IV over 15 minutes on days 1-2. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies	INDUCTION/RE-INDUCTIONI: Patients receive vorinostat PO 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: 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. TRANSPLANT: Patients may undergo an allogeneic transplant after induction therapy or consolidation therapy. (Permanently closed to accrual, effective 6/2/2015) Patients previously randomized to Arm III may continue treatment with or without vorinostat. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic transplant Cytarabine: Given IV Idarubicin: Given IV Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	261	261	216
Number (95% Confidence Interval) [Proportion of participants]	0.48 0.2%	0.51 0.2%	0.46 0.2%

Adverse Events

Time Frame	Up to 5 years
Adverse Event Reporting Description	Number of patients with adverse events are reported by type of adverse event. All adverse events, regardless of attribution or grade, are reported. Adverse events are reported for eligible patients who started treatment.
Arm/Group Title	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)		Arm II (High-dose Cytarabine, Idarubicin)		Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive standard dose cytarabine 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 CR or CRi may proceed to allogeneic HSCT or to consolidation therapy.		INDUCTION/RE-INDUCTION: 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.		INDUCTION/RE-INDUCTION: Patients receive vorinostat PO 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.
All Cause Mortality
	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)		Arm II (High-dose Cytarabine, Idarubicin)		Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	126/261 (48.3%)		114/259 (44%)		103/211 (48.8%)
Serious Adverse Events
	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)		Arm II (High-dose Cytarabine, Idarubicin)		Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/261 (4.2%)		27/259 (10.4%)		75/211 (35.5%)
Blood and lymphatic system disorders
Febrile neutropenia	1/261 (0.4%)		4/259 (1.5%)		13/211 (6.2%)
Leukocytosis	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Cardiac disorders
Atrial fibrillation	0/261 (0%)		2/259 (0.8%)		1/211 (0.5%)
Atrial flutter	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Cardiac arrest	1/261 (0.4%)		4/259 (1.5%)		2/211 (0.9%)
Heart failure	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Pericardial effusion	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Pericardial tamponade	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Sinus tachycardia	0/261 (0%)		1/259 (0.4%)		3/211 (1.4%)
Supraventricular tachycardia	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Gastrointestinal disorders
Abdominal distension	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Abdominal pain	0/261 (0%)		0/259 (0%)		5/211 (2.4%)
Colitis	0/261 (0%)		0/259 (0%)		6/211 (2.8%)
Colonic hemorrhage	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Colonic perforation	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Diarrhea	0/261 (0%)		0/259 (0%)		6/211 (2.8%)
Enterocolitis	0/261 (0%)		2/259 (0.8%)		2/211 (0.9%)
Esophageal hemorrhage	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Esophagitis	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Fecal incontinence	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Gastric hemorrhage	0/261 (0%)		1/259 (0.4%)		1/211 (0.5%)
Gastritis	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Gastrointestinal disorders-Other	0/261 (0%)		1/259 (0.4%)		1/211 (0.5%)
Ileus	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Jejunal obstruction	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Lower gastrointestinal hemorrhage	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Mucositis oral	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Nausea	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Typhlitis	1/261 (0.4%)		0/259 (0%)		7/211 (3.3%)
Vomiting	1/261 (0.4%)		0/259 (0%)		1/211 (0.5%)
General disorders
Death NOS	2/261 (0.8%)		1/259 (0.4%)		1/211 (0.5%)
Edema limbs	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Edema trunk	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Gait disturbance	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
General disorders and admin site conditions - Other	0/261 (0%)		1/259 (0.4%)		0/211 (0%)
Multi-organ failure	1/261 (0.4%)		2/259 (0.8%)		4/211 (1.9%)
Neck edema	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Hepatobiliary disorders
Cholecystitis	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Hepatic failure	1/261 (0.4%)		0/259 (0%)		0/211 (0%)
Hepatobiliary disorders-Other	1/261 (0.4%)		0/259 (0%)		1/211 (0.5%)
Immune system disorders
Allergic reaction	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Infections and infestations
Enterocolitis infectious	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Infections and infestations-Other	0/261 (0%)		0/259 (0%)		5/211 (2.4%)
Lip infection	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Lung infection	0/261 (0%)		1/259 (0.4%)		4/211 (1.9%)
Sepsis	1/261 (0.4%)		11/259 (4.2%)		17/211 (8.1%)
Upper respiratory infection	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Urinary tract infection	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Investigations
Activated partial thromboplastin time prolonged	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Alanine aminotransferase increased	0/261 (0%)		0/259 (0%)		6/211 (2.8%)
Alkaline phosphatase increased	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Aspartate aminotransferase increased	0/261 (0%)		0/259 (0%)		5/211 (2.4%)
Blood bilirubin increased	0/261 (0%)		1/259 (0.4%)		7/211 (3.3%)
Cardiac troponin I increased	0/261 (0%)		1/259 (0.4%)		0/211 (0%)
Creatinine increased	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Ejection fraction decreased	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Electrocardiogram QT corrected interval prolonged	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Fibrinogen decreased	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
GGT increased	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
INR increased	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Platelet count decreased	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Weight gain	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Weight loss	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Metabolism and nutrition disorders
Acidosis	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Alkalosis	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Anorexia	0/261 (0%)		0/259 (0%)		5/211 (2.4%)
Dehydration	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Hyperglycemia	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Hypernatremia	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Hypoalbuminemia	1/261 (0.4%)		0/259 (0%)		3/211 (1.4%)
Hypocalcemia	1/261 (0.4%)		0/259 (0%)		4/211 (1.9%)
Hypokalemia	1/261 (0.4%)		0/259 (0%)		6/211 (2.8%)
Hyponatremia	1/261 (0.4%)		0/259 (0%)		2/211 (0.9%)
Hypophosphatemia	0/261 (0%)		1/259 (0.4%)		2/211 (0.9%)
Tumor lysis syndrome	0/261 (0%)		1/259 (0.4%)		4/211 (1.9%)
Musculoskeletal and connective tissue disorders
Back pain	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Generalized muscle weakness	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Musculoskeletal and connective tiss disorder - Other	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Myalgia	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Pain in extremity	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Nervous system disorders
Ataxia	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Edema cerebral	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Encephalopathy	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Headache	1/261 (0.4%)		0/259 (0%)		0/211 (0%)
Intracranial hemorrhage	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Ischemia cerebrovascular	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Nervous system disorders-Other	1/261 (0.4%)		1/259 (0.4%)		0/211 (0%)
Paresthesia	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Peripheral sensory neuropathy	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Reversible posterior leukoencephalopathy syndrome	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Seizure	1/261 (0.4%)		0/259 (0%)		2/211 (0.9%)
Somnolence	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Stroke	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Vasovagal reaction	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Renal and urinary disorders
Acute kidney injury	2/261 (0.8%)		4/259 (1.5%)		9/211 (4.3%)
Urinary incontinence	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Reproductive system and breast disorders
Genital edema	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/261 (0.4%)		3/259 (1.2%)		4/211 (1.9%)
Bronchopulmonary hemorrhage	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Dyspnea	0/261 (0%)		1/259 (0.4%)		2/211 (0.9%)
Hypoxia	0/261 (0%)		2/259 (0.8%)		5/211 (2.4%)
Pleural effusion	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Pulmonary edema	0/261 (0%)		1/259 (0.4%)		5/211 (2.4%)
Resp, thoracic and mediastinal disorders - Other	0/261 (0%)		1/259 (0.4%)		1/211 (0.5%)
Respiratory failure	3/261 (1.1%)		6/259 (2.3%)		15/211 (7.1%)
Skin and subcutaneous tissue disorders
Erythroderma	0/261 (0%)		0/259 (0%)		1/211 (0.5%)
Rash maculo-papular	0/261 (0%)		0/259 (0%)		2/211 (0.9%)
Vascular disorders
Hematoma	0/261 (0%)		1/259 (0.4%)		0/211 (0%)
Hypertension	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Hypotension	0/261 (0%)		2/259 (0.8%)		8/211 (3.8%)
Thromboembolic event	0/261 (0%)		0/259 (0%)		3/211 (1.4%)
Other (Not Including Serious) Adverse Events
	Arm I (Standard Dose Cytarabine, Daunorubicin Hydrochloride)		Arm II (High-dose Cytarabine, Idarubicin)		Arm III (Vorinostat, High-dose Cytarabine, Idarubicin)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	249/261 (95.4%)		254/259 (98.1%)		206/211 (97.6%)
Blood and lymphatic system disorders
Anemia	185/261 (70.9%)		185/259 (71.4%)		137/211 (64.9%)
Febrile neutropenia	158/261 (60.5%)		170/259 (65.6%)		120/211 (56.9%)
Cardiac disorders
Sinus bradycardia	11/261 (4.2%)		9/259 (3.5%)		12/211 (5.7%)
Sinus tachycardia	44/261 (16.9%)		47/259 (18.1%)		30/211 (14.2%)
Ear and labyrinth disorders
Ear pain	16/261 (6.1%)		7/259 (2.7%)		2/211 (0.9%)
Eye disorders
Blurred vision	15/261 (5.7%)		13/259 (5%)		16/211 (7.6%)
Eye disorders-Other	16/261 (6.1%)		15/259 (5.8%)		8/211 (3.8%)
Gastrointestinal disorders
Abdominal distension	13/261 (5%)		7/259 (2.7%)		11/211 (5.2%)
Abdominal pain	59/261 (22.6%)		93/259 (35.9%)		76/211 (36%)
Bloating	12/261 (4.6%)		16/259 (6.2%)		9/211 (4.3%)
Colitis	5/261 (1.9%)		15/259 (5.8%)		10/211 (4.7%)
Constipation	80/261 (30.7%)		47/259 (18.1%)		42/211 (19.9%)
Diarrhea	129/261 (49.4%)		213/259 (82.2%)		157/211 (74.4%)
Dry mouth	28/261 (10.7%)		19/259 (7.3%)		20/211 (9.5%)
Dyspepsia	19/261 (7.3%)		14/259 (5.4%)		22/211 (10.4%)
Dysphagia	21/261 (8%)		17/259 (6.6%)		14/211 (6.6%)
Gastroesophageal reflux disease	16/261 (6.1%)		17/259 (6.6%)		14/211 (6.6%)
Gastrointestinal disorders-Other	15/261 (5.7%)		19/259 (7.3%)		11/211 (5.2%)
Hemorrhoids	16/261 (6.1%)		7/259 (2.7%)		17/211 (8.1%)
Mucositis oral	95/261 (36.4%)		92/259 (35.5%)		66/211 (31.3%)
Nausea	146/261 (55.9%)		181/259 (69.9%)		147/211 (69.7%)
Oral hemorrhage	14/261 (5.4%)		2/259 (0.8%)		6/211 (2.8%)
Oral pain	30/261 (11.5%)		22/259 (8.5%)		13/211 (6.2%)
Typhlitis	10/261 (3.8%)		14/259 (5.4%)		18/211 (8.5%)
Vomiting	69/261 (26.4%)		124/259 (47.9%)		93/211 (44.1%)
General disorders
Chills	47/261 (18%)		46/259 (17.8%)		37/211 (17.5%)
Edema face	12/261 (4.6%)		13/259 (5%)		9/211 (4.3%)
Edema limbs	71/261 (27.2%)		89/259 (34.4%)		45/211 (21.3%)
Fatigue	138/261 (52.9%)		143/259 (55.2%)		105/211 (49.8%)
Fever	77/261 (29.5%)		83/259 (32%)		55/211 (26.1%)
General disorders and admin site conditions - Other	16/261 (6.1%)		29/259 (11.2%)		9/211 (4.3%)
Infusion related reaction	15/261 (5.7%)		13/259 (5%)		6/211 (2.8%)
Malaise	7/261 (2.7%)		13/259 (5%)		4/211 (1.9%)
Non-cardiac chest pain	26/261 (10%)		20/259 (7.7%)		16/211 (7.6%)
Pain	27/261 (10.3%)		34/259 (13.1%)		17/211 (8.1%)
Infections and infestations
Catheter related infection	6/261 (2.3%)		8/259 (3.1%)		12/211 (5.7%)
Infections and infestations-Other	37/261 (14.2%)		46/259 (17.8%)		31/211 (14.7%)
Lung infection	32/261 (12.3%)		34/259 (13.1%)		24/211 (11.4%)
Sepsis	22/261 (8.4%)		20/259 (7.7%)		21/211 (10%)
Injury, poisoning and procedural complications
Bruising	11/261 (4.2%)		15/259 (5.8%)		9/211 (4.3%)
Investigations
Activated partial thromboplastin time prolonged	11/261 (4.2%)		19/259 (7.3%)		11/211 (5.2%)
Alanine aminotransferase increased	99/261 (37.9%)		109/259 (42.1%)		87/211 (41.2%)
Alkaline phosphatase increased	69/261 (26.4%)		70/259 (27%)		66/211 (31.3%)
Aspartate aminotransferase increased	89/261 (34.1%)		108/259 (41.7%)		94/211 (44.5%)
Blood bilirubin increased	68/261 (26.1%)		90/259 (34.7%)		72/211 (34.1%)
Creatinine increased	20/261 (7.7%)		32/259 (12.4%)		35/211 (16.6%)
INR increased	36/261 (13.8%)		53/259 (20.5%)		29/211 (13.7%)
Investigations-Other	13/261 (5%)		20/259 (7.7%)		11/211 (5.2%)
Lymphocyte count decreased	98/261 (37.5%)		113/259 (43.6%)		84/211 (39.8%)
Neutrophil count decreased	155/261 (59.4%)		139/259 (53.7%)		112/211 (53.1%)
Platelet count decreased	185/261 (70.9%)		180/259 (69.5%)		142/211 (67.3%)
Weight loss	40/261 (15.3%)		37/259 (14.3%)		40/211 (19%)
White blood cell decreased	163/261 (62.5%)		154/259 (59.5%)		121/211 (57.3%)
Metabolism and nutrition disorders
Anorexia	81/261 (31%)		103/259 (39.8%)		84/211 (39.8%)
Hyperglycemia	92/261 (35.2%)		98/259 (37.8%)		89/211 (42.2%)
Hyperkalemia	15/261 (5.7%)		21/259 (8.1%)		11/211 (5.2%)
Hypermagnesemia	13/261 (5%)		17/259 (6.6%)		14/211 (6.6%)
Hypernatremia	13/261 (5%)		16/259 (6.2%)		19/211 (9%)
Hypoalbuminemia	127/261 (48.7%)		130/259 (50.2%)		99/211 (46.9%)
Hypocalcemia	99/261 (37.9%)		109/259 (42.1%)		100/211 (47.4%)
Hypoglycemia	6/261 (2.3%)		4/259 (1.5%)		11/211 (5.2%)
Hypokalemia	109/261 (41.8%)		127/259 (49%)		98/211 (46.4%)
Hypomagnesemia	41/261 (15.7%)		49/259 (18.9%)		39/211 (18.5%)
Hyponatremia	93/261 (35.6%)		106/259 (40.9%)		68/211 (32.2%)
Hypophosphatemia	71/261 (27.2%)		91/259 (35.1%)		69/211 (32.7%)
Musculoskeletal and connective tissue disorders
Back pain	36/261 (13.8%)		29/259 (11.2%)		24/211 (11.4%)
Generalized muscle weakness	20/261 (7.7%)		15/259 (5.8%)		18/211 (8.5%)
Neck pain	14/261 (5.4%)		6/259 (2.3%)		7/211 (3.3%)
Pain in extremity	26/261 (10%)		25/259 (9.7%)		22/211 (10.4%)
Nervous system disorders
Dizziness	34/261 (13%)		22/259 (8.5%)		33/211 (15.6%)
Dysgeusia	26/261 (10%)		38/259 (14.7%)		31/211 (14.7%)
Headache	74/261 (28.4%)		70/259 (27%)		51/211 (24.2%)
Psychiatric disorders
Anxiety	41/261 (15.7%)		62/259 (23.9%)		35/211 (16.6%)
Confusion	11/261 (4.2%)		16/259 (6.2%)		10/211 (4.7%)
Depression	19/261 (7.3%)		28/259 (10.8%)		14/211 (6.6%)
Insomnia	49/261 (18.8%)		51/259 (19.7%)		39/211 (18.5%)
Renal and urinary disorders
Acute kidney injury	9/261 (3.4%)		19/259 (7.3%)		26/211 (12.3%)
Hematuria	14/261 (5.4%)		17/259 (6.6%)		21/211 (10%)
Respiratory, thoracic and mediastinal disorders
Cough	51/261 (19.5%)		48/259 (18.5%)		40/211 (19%)
Dyspnea	55/261 (21.1%)		54/259 (20.8%)		40/211 (19%)
Epistaxis	35/261 (13.4%)		37/259 (14.3%)		27/211 (12.8%)
Hiccups	5/261 (1.9%)		14/259 (5.4%)		16/211 (7.6%)
Hypoxia	10/261 (3.8%)		18/259 (6.9%)		13/211 (6.2%)
Nasal congestion	20/261 (7.7%)		14/259 (5.4%)		12/211 (5.7%)
Pleural effusion	16/261 (6.1%)		17/259 (6.6%)		19/211 (9%)
Productive cough	10/261 (3.8%)		18/259 (6.9%)		9/211 (4.3%)
Pulmonary edema	11/261 (4.2%)		15/259 (5.8%)		8/211 (3.8%)
Resp, thoracic and mediastinal disorders - Other	7/261 (2.7%)		20/259 (7.7%)		10/211 (4.7%)
Sore throat	34/261 (13%)		18/259 (6.9%)		18/211 (8.5%)
Skin and subcutaneous tissue disorders
Alopecia	46/261 (17.6%)		41/259 (15.8%)		46/211 (21.8%)
Dry skin	16/261 (6.1%)		29/259 (11.2%)		22/211 (10.4%)
Erythema multiforme	8/261 (3.1%)		13/259 (5%)		4/211 (1.9%)
Periorbital edema	6/261 (2.3%)		14/259 (5.4%)		3/211 (1.4%)
Pruritus	38/261 (14.6%)		58/259 (22.4%)		42/211 (19.9%)
Purpura	11/261 (4.2%)		15/259 (5.8%)		6/211 (2.8%)
Rash acneiform	11/261 (4.2%)		13/259 (5%)		9/211 (4.3%)
Rash maculo-papular	94/261 (36%)		117/259 (45.2%)		82/211 (38.9%)
Skin and subcutaneous tissue disorders - Other	29/261 (11.1%)		39/259 (15.1%)		25/211 (11.8%)
Vascular disorders
Hypertension	38/261 (14.6%)		54/259 (20.8%)		27/211 (12.8%)
Hypotension	39/261 (14.9%)		45/259 (17.4%)		28/211 (13.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.