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Allogeneic Hematopoietic Stem Cell Transplantation (AlloSCT) Initial Salvage Therapy for Induction Failure Acute Myeloid Leukemia (AML)

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ClinicalTrials.gov Identifier: NCT02441803
Recruitment Status : Active, not recruiting
First Posted : May 12, 2015
Last Update Posted : July 31, 2018
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

Objectives:

Primary Objectives:

  1. To determine the safety and feasibility of allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage treatment for patients with primary induction failure (PIF) acute myeloid leukemia (AML).
  2. To determine efficacy of AHSCT following decitabine, clofarabine, idarubicin, and cytarabine (DCIA) salvage chemotherapy evaluated by overall response rate (RR), defined as complete response (CR) or CR without platelet recovery (CRp) or CR with insufficient hematological recovery (CRi).

Secondary Objectives:

  1. To determine the percentage of patients with PIF AML eligible for AHSCT after up to 2 courses of induction chemotherapy.
  2. To determine the early treatment-related mortality (TRM) (within first 4 weeks of first salvage chemotherapy regimen with DCIA and day 100 TRM after AHSCT.
  3. To determine the efficacy DCIA regimen as salvage chemotherapy for patients with PIF AML (% of patients who achieve </=5% bone marrow blasts prior to AHSCT.
  4. To determine the TRM at 1 year, relapse rate (RR), overall survival (OS) and event-free survival (EFS) for patients with PIF AML treated with DCIA followed by early AHSCT.

Condition or disease Intervention/treatment Phase
Leukemia Drug: Busulfan Drug: Fludarabine Drug: Clofarabine Radiation: Total Body Irradiation (TBI) Drug: Thymoglobulin Biological: Stem Cell Infusion Drug: Cyclophosphamide Drug: Tacrolimus Drug: Mycophenolate mofetil Drug: Decitabine Drug: Cytarabine Drug: Idarubicin Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Stem Cell Transplantation as Initial Salvage Therapy for Patients With Primary Induction Failure Acute Myeloid Leukemia Refractory to High-Dose Cytarabine-Based Induction Chemotherapy
Actual Study Start Date : September 14, 2015
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2023


Arm Intervention/treatment
Experimental: Matched Sibling Donor Group

Salvage Chemotherapy Before Transplant: Decitabine 20 mg/m2 by vein on Days 1 - 5. Cytarabine 1 g/m2 by vein on Days 6 - 10. Idarubicin 10 mg/m2 by vein on Days 6 - 8. Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Test dose Busulfan 32 mg/m2 by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3. Fludarabine 10 mg/m2 by vein on Days -6 to -3. Clofarabine 40 mg/m2 by vein on Days -6 to -3. Stem cell infusion performed on Day 0.

Drug: Busulfan
Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3.
Other Names:
  • Busulfex
  • Myleran

Drug: Fludarabine
Fludarabine 10 mg/m2 by vein on Days -6 to -3.
Other Names:
  • Fludarabine Phosphate
  • Fludara

Drug: Clofarabine

Salvage Chemotherapy Before Transplant: Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Clofarabine 40 mg/m2 by vein on Days -6 to -3.

Other Names:
  • Clofarex
  • Clolar

Biological: Stem Cell Infusion
Fresh or cryopreserved bone marrow or peripheral blood (PB) progenitor cells infused on Day 0. Goal is to infuse 4 X 106 CD34+ cells/kg if PB or >3.0 X 108 marrow mononuclear cells/kg if bone marrow.

Drug: Decitabine
20 mg/m2 by vein on Days 1 - 5.
Other Name: Dacogen

Drug: Cytarabine
1 g/m2 by vein on Days 6 - 10.
Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride

Drug: Idarubicin
10 mg/m2 by vein on Days 6 - 8.
Other Name: Idamycin

Experimental: Haploidentical Donor Group

Salvage Chemotherapy Before Transplant: Decitabine 20 mg/m2 by vein on Days 1 - 5. Cytarabine 1 g/m2 by vein on Days 6 - 10. Idarubicin 10 mg/m2 by vein on Days 6 - 8. Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3. Fludarabine 10 mg/m2 by vein on Days -6 to -3. Clofarabine 40 mg/m2 by vein on Days -6 to -3. Total body irradiation (TBI) delivered at 2Gy on Day -2. Stem cell infusion performed on Day 0. Cyclophosphamide 50 mg/kg by vein on Days +3 and +4. Tacrolimus 0.015 mg/kg/day by vein or mouth on Day +5. Mycophenolate mofetil 15 mg/kg/dose by vein or by mouth three times a day from Day +5 to Day+100.

Drug: Busulfan
Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3.
Other Names:
  • Busulfex
  • Myleran

Drug: Fludarabine
Fludarabine 10 mg/m2 by vein on Days -6 to -3.
Other Names:
  • Fludarabine Phosphate
  • Fludara

Drug: Clofarabine

Salvage Chemotherapy Before Transplant: Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Clofarabine 40 mg/m2 by vein on Days -6 to -3.

Other Names:
  • Clofarex
  • Clolar

Radiation: Total Body Irradiation (TBI)
Total body irradiation (TBI) delivered at 2Gy on Day -2.
Other Names:
  • TBI
  • XRT

Biological: Stem Cell Infusion
Fresh or cryopreserved bone marrow or peripheral blood (PB) progenitor cells infused on Day 0. Goal is to infuse 4 X 106 CD34+ cells/kg if PB or >3.0 X 108 marrow mononuclear cells/kg if bone marrow.

Drug: Cyclophosphamide
Cyclophosphamide 50 mg/kg by vein on Days +3 and +4.
Other Names:
  • Cytoxan
  • Neosar

Drug: Tacrolimus
Tacrolimus 0.015 mg/kg/day by vein or mouth on Day +5.
Other Name: Prograf

Drug: Mycophenolate mofetil
Mycophenolate mofetil 15 mg/kg/dose by vein or by mouth three times a day from Day +5 to Day+100.
Other Names:
  • MMF
  • CellCept

Drug: Decitabine
20 mg/m2 by vein on Days 1 - 5.
Other Name: Dacogen

Drug: Cytarabine
1 g/m2 by vein on Days 6 - 10.
Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride

Drug: Idarubicin
10 mg/m2 by vein on Days 6 - 8.
Other Name: Idamycin

Experimental: Matched Unrelated Donor Group

Salvage Chemotherapy Before Transplant: Decitabine 20 mg/m2 by vein on Days 1 - 5. Cytarabine 1 g/m2 by vein on Days 6 - 10. Idarubicin 10 mg/m2 by vein on Days 6 - 8. Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3. Fludarabine 10 mg/m2 by vein on Days -6 to -3. Clofarabine 40 mg/m2 by vein on Days -6 to -3. Thymoglobulin 2.0 mg/Kg by vein on Days -3 and -2. Stem cell infusion performed on Day 0.

Drug: Busulfan
Test dose Busulfan 32 mg/m2 given by vein on Day -8. Busulfan AUC 5,000 by vein on Days -6 to -3.
Other Names:
  • Busulfex
  • Myleran

Drug: Fludarabine
Fludarabine 10 mg/m2 by vein on Days -6 to -3.
Other Names:
  • Fludarabine Phosphate
  • Fludara

Drug: Clofarabine

Salvage Chemotherapy Before Transplant: Clofarabine 15 mg/m2 by vein on Days 6 - 9.

Stem Cell Transplant: Clofarabine 40 mg/m2 by vein on Days -6 to -3.

Other Names:
  • Clofarex
  • Clolar

Drug: Thymoglobulin
Thymoglobulin 2.0 mg/Kg by vein on Days -3 and -2.
Other Names:
  • ATG (Rabbit)
  • Rabbit Antithymocyte Globulin
  • Rabbit Antilymphocyte Globulin
  • Rabbit ATG
  • rATG

Biological: Stem Cell Infusion
Fresh or cryopreserved bone marrow or peripheral blood (PB) progenitor cells infused on Day 0. Goal is to infuse 4 X 106 CD34+ cells/kg if PB or >3.0 X 108 marrow mononuclear cells/kg if bone marrow.

Drug: Decitabine
20 mg/m2 by vein on Days 1 - 5.
Other Name: Dacogen

Drug: Cytarabine
1 g/m2 by vein on Days 6 - 10.
Other Names:
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine Arabinosine Hydrochloride

Drug: Idarubicin
10 mg/m2 by vein on Days 6 - 8.
Other Name: Idamycin




Primary Outcome Measures :
  1. Overall Response (OR) [ Time Frame: 4 months ]
    Participants classified as achieving overall response if they have complete response (CR) or CR without platelet recovery (CRp) or CR with insufficient hematological recovery (CRi) 4 months after initial treatment. Overall response (CR + CRp + CRi) rates and their posterior 95% credible intervals estimated using a beta distribution with a prior of Beta (0.4, 1.6).

  2. Treatment-Related Mortality (TRM) [ Time Frame: 4 months ]
    Participants classified as having treatment-related death if they die due to a symptom that is possibly, probably, or definitely related to therapy within 4 months of starting treatment. TRM rate at 4 months post treatment initiation reported using a prior of Beta (1.2, 0.8).


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 2 years ]
    OS defined as the time from starting treatment until death from any cause. Patients who are alive at the time of analysis will be censored on the date of last contact.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients age 18-60 years.
  2. Patients with diagnosis of AML, judged primary refractory after up to 2 courses of AML induction therapy (> 5% blasts on day 21 (+/-7 days) bone marrow aspirate and/or biopsy from the beginning of induction chemotherapy, up to 42 days).
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2.
  4. Adequate major organ function:, defined as: a) Serum creatinine </= 3 mg/dL; b) Total bilirubin </= 2.5 mg/dL; c) ALT (SGPT) </= 3 x ULN or </= 5 x ULN if related to disease; d) Cardiac ejection fraction >/= 40% (by either ECHO or MUGA).
  5. Willingness to have an allogeneic transplant.
  6. Patient or patient's legal representative able to provide written informed consent.
  7. Patients are required to meet the following criteria to proceed to AHSCT:
  8. Donor criteria: Availability of a donor either an HLA matched sibling donor (MSD) or a haploidentical (5-9/10 HLA matched); alternatively a 8/8 HLA matched unrelated donor (MUD) by high resolution typing is immediately available;
  9. Disease criteria: Day 21 (+/-7 days) bone marrow aspiration or biopsy from the beginning of salvage DCIA: a. In complete morphologic remission with <5% bone marrow blasts, or b. Aplastic (<10% bone marrow cellularity), and cytopenic with an absolute neutrophil count (ANC) less than 1,000/µL, or c. Low disease burden with < 30% BM blasts, with recovery of peripheral blood (PB) WBC (ANC>1,000/µL) and <5% circulating blasts.
  10. Adequate organ function criteria: a. Serum creatinine clearance >/= 50 ml/min (calculated by Cockcroft-Gault formula); b. Total bilirubin </= 2 times upper limit of normal (x ULN) (3 x ULN if considered to be due to leukemic involvement or Gilbert's syndrome); c. Alanine aminotransferase (ALT) </= 3 x ULN (5.0 x ULN if considered to be due to leukemic involvement); d. LVEF >/= 40% on ECHO or MUGA; e. DLCO >/= 50% predicted after correction for hemoglobin (must be performed in patients with history of smoking or lung disease;); DLCO may be omitted in patients without history of pulmonary disease if approved by the Study Chair.
  11. No active infection: Patients should be afebrile. If present, pulmonary infiltrates or other sites of infection must be improving on antibiotics. Patients should not require oxygen. Study Chair will be the arbiter of this criterion.

Exclusion Criteria:

  1. HIV positive; active hepatitis B or C.
  2. Uncontrolled active infections (viral, bacterial, and fungal); the Study Chair will be the final arbiter of this criterion.
  3. Patients with active secondary malignancy unless approved by the Study Chair.
  4. Liver cirrhosis.
  5. Active CNS involvement within the previous 2 months.
  6. Prior induction therapy with DAC + CIA.
  7. Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.
  8. Breast feeding women.
  9. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential.
  10. Inability to comply with medical therapy or follow-up.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02441803


Locations
United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
Principal Investigator: Stefan Ciurea, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02441803     History of Changes
Other Study ID Numbers: 2014-0358
NCI-2015-00849 ( Registry Identifier: NCI CTRP )
First Posted: May 12, 2015    Key Record Dates
Last Update Posted: July 31, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Leukemia
Acute myeloid leukemia
AML
Refractory
Allogeneic hematopoietic stem cell transplantation
AHSCT
Busulfan
Busulfex
Myleran
Fludarabine
Fludarabine Phosphate
Fludara
Clofarabine
Clofarex
Clolar
Total body irradiation
TBI
XRT
Thymoglobulin
ATG (Rabbit)
Rabbit antithymocyte Globulin
Rabbit Antilymphocyte Globulin
Rabbit ATG
rATG
Stem cell infusion
Cyclophosphamide
Cytoxan
Neosar
Tacrolimus
Prograf

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Tacrolimus
Fludarabine phosphate
Cytarabine
Busulfan
Thymoglobulin
Antilymphocyte Serum
Fludarabine
Decitabine
Clofarabine
Mycophenolic Acid
Azacitidine
Idarubicin
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors