- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00703820
Clofarabine Plus Cytarabine Versus Conventional Induction Therapy And A Study Of NK Cell Transplantation In Newly Diagnosed Acute Myeloid Leukemia
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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
- To estimate the event-free survival (EFS) of standard risk (SR) patients who receive chemotherapy alone and the EFS of SR patients who receive chemotherapy followed by natural killer (NK) cell transplantation.
Exploratory Objectives:
- To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and after induction therapy, and to explore the associations of these features with treatment outcome
- To assess the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of induction I
- To validate new markers and methods for minimal residual disease (MRD) detection
- To identify new prognostic factors by applying new technologies to study patient material
- To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol
- To describe the impact of antibiotic and antifungal prophylaxis on invasive bacterial and fungal infections, febrile neutropenia, hospitalization, and antibiotic resistance.
- To determine the performance characteristics of broad-range, molecular diagnostic methods for detection of bacterial, fungal, and viral agents, in comparison to methods currently in routine clinical use
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)
- Core binding factor (CBF) leukemia [t(8;21)/AML1-ETO or inv(16)/t(16;16)/CBF-MYH11,] and MRD < 0.1% at day 22,regardless of other genetic features.
- Patients with CBF leukemia who have MRD ≥ to 0.1% at day 22 or who have increasing levels of fusion transcript will be considered SR and thus eligible for NK cell therapy.
Standard-risk (SR) criteria (eligible for NK cell therapy)
- Absence of low-risk or high-risk features.
- CBF leukemia with MRD ≥ 0.1% at day 22 or increasing levels of fusion transcript
- FLT3-ITD and MRD < 0.1% at day 22
High-risk (HR) criteria (candidates for SCT; eligible for NK cell therapy)
Presence of one of the following features:
- t(6;9), t(8;16), t(16;21), -7, -5, or 5q-
- FAB M0 or M6
- FAB M7 without t(1;22)
- Treatment-related (secondary) AML
- RAEB-2 or AML arising from prior MDS
- FLT3-ITD and MRD ≥ 0.1% at day 22
- All other patients with poor response to therapy (must have one of the following features) MRD ≥ to 5% at day 22 MRD ≥ to 0.1% after Induction II
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.
Consolidation I:
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)
Consolidation II:
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.
CNS therapy
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
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Singapore, Singapore, 119228
- National University Health System
-
-
-
-
California
-
Palo Alto, California, United States, 94304
- Stanford University Medical Center
-
San Diego, California, United States, 92123
- Rady Children's Hospital
-
-
Illinois
-
Chicago, Illinois, United States, 60637
- University of Chicago
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02215-5450
- Dana Farber Cancer Institute and Children's Hospital
-
-
Michigan
-
Detroit, Michigan, United States, 48201
- Children's Hospital of Michigan
-
-
Tennessee
-
Memphis, Tennessee, United States, 38105
- St. Jude Children's Research Hospital
-
-
Texas
-
Fort Worth, Texas, United States, 76104
- Cook's Children's Medical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age less than or equal to 21 years at time of study entry.
- No prior therapy for this malignancy except for one dose of intrathecal therapy and the use of hydroxyurea or low-dose cytarabine (100-200 mg/m2 per day for one week or less ) for hyperleukocytosis.
- Written informed consent according to institutional guidelines
- Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
- Male and female participants must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
Exclusion Criteria:
- Down syndrome
- Acute Promyelocytic Leukemia (APL)
- Juvenile Myelomonocytic Leukemia (JMML)
- Fanconi anemia (FA)
- Kostmann syndrome
- Shwachman syndrome
- Other bone marrow failure syndromes
- Use of concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
- Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry with the exception of IT therapy, hydroxyurea, or low-dose cytarabine as stated above. The patient must have recovered from all acute toxicities from any previous therapy.
- Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
- Pregnant or lactating patients.
- Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: ADE
Cytarabine + Daunorubicin + Etoposide NK cells for infusion are prepared using the CliniMACS System. |
See Detailed Description
Other Names:
See Detailed Description
Other Names:
See Detailed Description
Other Names:
The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS).
The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g.
apheresis products).
These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
Other Names:
|
Active Comparator: Clo/AraC
Clofarabine + Cytarabine NK cells for infusion are prepared using the CliniMACS System. |
See Detailed Description
Other Names:
The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS).
The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g.
apheresis products).
These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
Other Names:
See Detailed Description
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Day 22 MRD measurement after one course of therapy
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Event-free Survival of Standard Risk Patients Who Receive Chemotherapy Alone.
Time Frame: 3 years after completion of therapy
|
Kaplan-Meier estimate of the probability of being alive and free of relapse or second malignancy three years after protocol enrollment
|
3 years after completion of therapy
|
Event-free Survival of Standard Risk Patients Who Receive Chemotherapy Followed by Natural Killer Cell Transplantation.
Time Frame: 3 years after completion of therapy
|
Kaplan-Meier estimate of the probability of being alive and free of relapse or second malignancy three years after protocol enrollment
|
3 years after completion of therapy
|
Collaborators and Investigators
Investigators
- Principal Investigator: Jeffrey Rubnitz, MD, St. Jude Children's Research Hospital
Publications and helpful links
General Publications
- Rubnitz JE, Lacayo NJ, Inaba H, Heym K, Ribeiro RC, Taub J, McNeer J, Degar B, Schiff D, Yeoh AE, Coustan-Smith E, Wang L, Triplett B, Raimondi SC, Klco J, Choi J, Pounds S, Pui CH. Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial. J Clin Oncol. 2019 Aug 10;37(23):2072-2081. doi: 10.1200/JCO.19.00327. Epub 2019 Jun 27.
- Nguyen R, Wu H, Pounds S, Inaba H, Ribeiro RC, Cullins D, Rooney B, Bell T, Lacayo NJ, Heym K, Degar B, Schiff D, Janssen WE, Triplett B, Pui CH, Leung W, Rubnitz JE. A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia. J Immunother Cancer. 2019 Mar 20;7(1):81. doi: 10.1186/s40425-019-0564-6.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Antibiotics, Antineoplastic
- Etoposide
- Clofarabine
- Cytarabine
- Daunorubicin
Other Study ID Numbers
- 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)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Acute Myeloid Leukemia
-
University of PennsylvaniaActive, not recruitingAcute Myeloid Leukemia, in Relapse | Acute Myeloid Leukemia, Refractory | Acute Myeloid Leukemia, PediatricUnited States
-
Terrence J Bradley, MDImago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New...RecruitingAcute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Acute Myeloid Leukemia, in RelapseUnited States
-
National Cancer Institute (NCI)RecruitingAcute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Recurrent Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
-
Bhavana BhatnagarCTI BioPharmaCompletedRecurrent Adult Acute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Untreated Adult Acute Myeloid Leukemia | Therapy-Related Acute Myeloid LeukemiaUnited States
-
Washington University School of MedicineWithdrawnRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
-
C. Babis AndreadisGateway for Cancer Research; AVEO Pharmaceuticals, Inc.TerminatedAcute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
-
Massachusetts General HospitalExelixisCompletedRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI)RecruitingAcute Myeloid Leukemia | Recurrent Adult Acute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
-
Jacqueline Garcia, MDEli Lilly and CompanyCompletedCombination Merestinib and LY2874455 for Patients With Relapsed or Refractory Acute Myeloid LeukemiaRelapsed Adult Acute Myeloid Leukemia | Refractory Adult Acute Myeloid LeukemiaUnited States
-
University of NebraskaNational Cancer Institute (NCI)Active, not recruitingSecondary Acute Myeloid Leukemia | Therapy-Related Acute Myeloid Leukemia | Adult Acute Myeloid LeukemiaUnited States
Clinical Trials on Cytarabine
-
Sunesis PharmaceuticalsCompletedAcute Myeloid LeukemiaUnited States, Canada, Spain, Belgium, Korea, Republic of, Australia, France, Germany, Poland, New Zealand, United Kingdom, Czechia, Austria, Hungary, Italy
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)RecruitingRecurrent Chronic Myelomonocytic Leukemia | Refractory Chronic Myelomonocytic Leukemia | Blasts More Than 5 Percent of Bone Marrow Nucleated Cells | Recurrent High Risk Myelodysplastic Syndrome | Refractory High Risk Myelodysplastic Syndrome | Blasts 10-19 Percent of Bone Marrow Nucleated Cells and other conditionsUnited States
-
Jianxiang WangUnknownAcute Myeloid LeukemiaChina
-
Ohio State University Comprehensive Cancer CenterNational Cancer Institute (NCI)RecruitingRefractory Acute Myeloid Leukemia | Blasts More Than 5 Percent of Bone Marrow Nucleated Cells | Persistent DiseaseUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)CompletedAcute Myeloid Leukemia | Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome | Secondary Acute Myeloid LeukemiaUnited States
-
Roswell Park Cancer InstituteJazz PharmaceuticalsRecruitingAcute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome | Secondary Acute Myeloid Leukemia | Therapy-Related Acute Myeloid Leukemia | Acute Myeloid Leukemia With Myelodysplasia-Related ChangesUnited States
-
M.D. Anderson Cancer CenterRecruitingMyelodysplastic Syndrome | Recurrent Acute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Myeloproliferative Neoplasm | Acute Myeloid Leukemia With Gene MutationsUnited States
-
M.D. Anderson Cancer CenterRecruitingRecurrent Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
-
Institute of Hematology & Blood Diseases Hospital...Recruiting
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)RecruitingAcute Myeloid Leukemia | Recurrent Acute Myeloid Leukemia | Recurrent Myelodysplastic Syndrome | Refractory Acute Myeloid Leukemia | Refractory Myelodysplastic Syndrome | High Risk Myelodysplastic Syndrome | Blasts More Than 10 Percent of Bone Marrow Nucleated CellsUnited States