Clofarabine Plus Cytarabine Versus Conventional Induction Therapy And A Study Of NK Cell Transplantation In Newly Diagnosed Acute Myeloid Leukemia
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|ClinicalTrials.gov Identifier: NCT00703820|
Recruitment Status : Active, not recruiting
First Posted : June 24, 2008
Results First Posted : April 2, 2018
Last Update Posted : April 2, 2018
|First Submitted Date ICMJE||June 20, 2008|
|First Posted Date ICMJE||June 24, 2008|
|Results First Submitted Date||March 2, 2018|
|Results First Posted Date||April 2, 2018|
|Last Update Posted Date||April 2, 2018|
|Actual Study Start Date ICMJE||August 4, 2008|
|Actual Primary Completion Date||March 30, 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Day 22 Minimal Residual Disease (MRD) Measured by Flow Cytometry [ Time Frame: Day 22 MRD measurement after one course of therapy ]
MRD-negative is defined as <0.1% blasts with leukemia-associated phenotype detected by flow cytometry. MRD-positive is defined as >=0.1% blasts with leukemia-associated phenotype detected by flow cytometry.
|Original Primary Outcome Measures ICMJE
||To compare the immunologic complete response rate after one course of therapy in patients who receive cytarabine + daunorubicin + etoposide (ADE) with that in patients who receive clofarabine + cytarabine (Clo/AraC) [ Time Frame: Day 22 MRD measurement ]|
|Change History||Complete list of historical versions of study NCT00703820 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Clofarabine Plus Cytarabine Versus Conventional Induction Therapy And A Study Of NK Cell Transplantation In Newly Diagnosed Acute Myeloid Leukemia|
|Official Title ICMJE||AML08: A Phase II Randomized Trial of Clofarabine Plus Cytarabine Versus Conventional Induction Therapy And A Phase II Study Of Natural Killer Cell Transplantation In Patients With Newly Diagnosed Acute Myeloid Leukemia|
|Brief Summary||The purpose of this study is to assess the feasibility and efficacy of a novel form of therapy—haploidentical NK cell transplantation—in patients with standard-risk AML. In addition, we will investigate the efficacy of clofarabine + cytarabine (Clo/AraC) in newly diagnosed patients with AML and attempt to optimize outcome through the use of MRD-adapted therapy and further improvements in supportive care.|
The overall objective of this protocol is to improve the cure rate of acute myeloid leukemia (AML).
We will compare the immunologic complete response rate after one course of therapy in patients who receive cytarabine + daunorubicin + etoposide (ADE) with that in patients who receive clofarabine + cytarabine (Clo/AraC)
Secondary objectives include
Treatment will be based on cytogenetic and molecular characteristics, morphology, and response to therapy as assessed by flow cytometry. Risk groups are defined below. The general treatment plan will consist of chemotherapy for LR patients, chemotherapy ± NK cell therapy for SR patients, and chemotherapy + stem cell transplant (SCT) for HR patients. HR patients who do not have a suitable stem cell donor or who decline SCT will be eligible for NK cell therapy.
Low-risk (LR) criteria (not eligible for SCT or NK cell therapy)
Standard-risk (SR) criteria (eligible for NK cell therapy)
High-risk (HR) criteria (candidates for SCT; eligible for NK cell therapy)
Presence of one of the following features:
Induction therapy (2 courses)
All patients will receive two courses of induction therapy that will include one course of either high dose cytarabine, daunorubicin, and etoposide (HD-ADE) or one course of clofarabine and cytarabine (Clo/AraC), followed by one course of low dose cytarabine, daunorubicin, and etoposide (LD-ADE). Patients will be randomly assigned to receive one of the following induction regimens.
Induction I: HD-ADE
Cytarabine: 3 g/m2 IV over 3 hours q12 hours x 6 doses (days 1, 3, 5) Daunorubicin: 50 mg/m2 (1.67 mg/kg for patients less than 10 kg) IV over 6 hours on days 2, 4, 6 (3 doses) Etoposide: 100 mg/m2 IV over 4 hours on days 2-6 (5 doses)
Induction I: Clo/AraC
Clofarabine: 52 mg/m2 IV over 2 hours on days 1-5 (5 doses) Cytarabine: 1 gram/m2 IV over 2 hours on days 1-5 (5 doses; each dose to start 4 hours after the start of clofarabine)
Induction II: LD-ADE
Cytarabine: 100 mg/m2 IV over 30 minutes q12 hours on days 1-8 (16 doses), Daunorubicin: 50 mg/m2 (1.67 mg/kg for patients less than 10 kg) IV over 6 hours on days 2, 4, 6 (3 doses) Etoposide: 100 mg/m2 IV over 4 hours on days 1-5 (5 doses)
Induction II for patients with FLT3-ITD: LD-ADE + Sorafenib
Patients with FLT3-ITD will take Sorafenib, 400 mg/m2 per day, orally in two divided doses (200 mg/m2/dose BID) starting one day after the completion of Induction II and continuing for 21 days Patients with FLT3-ITD who do not experience toxicity related to Sorafenib will also receive a 21-day course of Sorafenib after subsequent courses of chemotherapy.
Induction II for other HR patients: LD-ADE + vorinostat
[NOTE: Collaborating institutions may elect to opt out of treatment with vorinostat. If a site opts out, then all applicable patients at that site will receive standard induction therapy with LD-ADE (without vorinostat).]
Patients with M7 AML without t(1;22) and other HR patients without FLT3-ITD will be treated with a combination of vorinostat and LD-ADE. Vorinostat will be given orally for 3 days (Days -2, -1, 0) prior to the initiation of Induction II chemotherapy.
Special subgroup HR patients with MRD < 0.1% may proceed directly to SCT after Induction I if a suitable donor is available and the transplant can be performed without delay.
Mitoxantrone: 12 mg/m2 (0.4 mg/kg for patients less than 10 kg) IV over 1 hour on days 3-5 (3 doses) Cytarabine: 1 g/m2 IV over 2 hours every 12 hours on days 1-4 (8 doses)
Cytarabine 3 g/m2 IV over 3 hours every 12 hours on days 1, 2, 8, 9 (8 doses). Erwinia Asparaginase 25,000 Units/m2 (833 Units/kg for infants < 1 month of age, or for infants < 3 months of age who were born significantly prematurely defined as < 36 weeks gestation) IM or IV over 1 hour, 3 hours after the 4th and 8th doses of cytarabine.
NK cell therapy Standard risk patients who have a KIR-mismatched family member who is greater than 18 years old will undergo NK cell transplantation. In addition, HR patients who do not have a suitable stem cell donor or who decline SCT will be eligible for NK cell therapy if they have a KIR-mismatched family member.
Treatment schema Day -7: Cyclophosphamide 60 mg/kg IV over 1 hour. Mesna 15 mg/kg/dose IV Days -6 through -2: Fludarabine 25 mg/m2/day IV over 30 minutes (5 doses) Days -1, +1, +3, +5, +7, +9: IL-2 1 million units/m2 given subcutaneously Day -1: Donor pheresis Day 0: NK cell infusion
No steroids, including the use of hydrocortisone as pre-medication, may be given to patients during the 3 days prior to the NK cell infusion or during the first 7 days after the infusion.
Triple intrathecal therapy with methotrexate, hydrocortisone, and cytarabine (MHA) will be used for all CNS therapy at the doses:
< 1 year methotrexate 6 mg, hydrocortisone 12 mg, cytarabine 18 mg, 1-2 years methotrexate 8 mg, hydrocortisone 16 mg, cytarabine 24 mg, 2-3 years methotrexate 10 mg, hydrocortisone 20 mg, cytarabine 30 mg, > 3 years methotrexate 12 mg, hydrocortisone 24 mg, cytarabine 36 mg
Leucovorin rescue (5 mg/m2 per dose; 5 mg maximum per dose) will be given orally or intravenously at 24 and 30 hours after each IT MHA treatment.
Patients with no evidence of CNS disease \[(i.e., no leukemic blast cells on cerebrospinal fluid (CSF) cytospin] will receive 4 total doses of intrathecal therapy, given at approximately one month intervals or at the beginning of each of the first 4 courses of chemotherapy.IT therapy will not be given before NK cell therapy.
Patients with overt CNS leukemia (less than or equal to 5 leukocytes per l of CSF and the presence of leukemic blast cells on CSF cytospin) will receive weekly intrathecal therapy until the CSF is free of blast cells (minimum number of doses, 4). These patients will then receive 4 additional doses of intrathecal therapy (minimum total number of doses, 8) at approximately 1-month intervals (generally given with each subsequent course of chemotherapy).IT therapy will not be given before NK cell therapy.
Patients with < 5 leukocytes per mul of CSF and the presence of leukemic blast cells on CSF cytospin (CNS2)will receive weekly intrathecal therapy until the CSF is free of blast cells. These patients will then receive 4 additional doses of intrathecal therapy at approximately 1-month intervals (generally given with each subsequent course of chemotherapy).IT therapy will not be given before NK cell therapy.
Patients who are unable to undergo lumbar puncture and receive intrathecal therapy prior to starting induction I should be treated as CNS2 unless they have overt CNS leukemia (CNS3).
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Acute Myeloid Leukemia|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date||June 30, 2020|
|Actual Primary Completion Date||March 30, 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||up to 21 Years (Child, Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Singapore, United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00703820|
|Other Study ID Numbers ICMJE||AML08
R01CA138744 ( U.S. NIH Grant/Contract )
R01CA115422 ( U.S. NIH Grant/Contract )
R01CA132946 ( U.S. NIH Grant/Contract )
NCI-2011-03659 ( Registry Identifier: NCI Clinical Trial Registration Program )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement||Not Provided|
|Responsible Party||St. Jude Children's Research Hospital|
|Study Sponsor ICMJE||St. Jude Children's Research Hospital|
|PRS Account||St. Jude Children's Research Hospital|
|Verification Date||March 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP