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

Information source: M.D. Anderson Cancer Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Leukemia

Intervention: Busulfan (Drug); Fludarabine (Drug); Clofarabine (Drug); Total Body Irradiation (TBI) (Radiation); Thymoglobulin (Drug); Stem Cell Infusion (Biological); Cyclophosphamide (Drug); Tacrolimus (Drug); Mycophenolate mofetil (Drug); Decitabine (Drug); Cytarabine (Drug); Idarubicin (Drug)

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Stefan Ciurea, MD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Stefan Ciurea, MD, Phone: 713-792-8750

Summary

Objectives: Primary Objectives: 1. To determine the safety and feasibility of allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage treatment for participants with primary induction failure (PIF) acute myeloid leukemia (AML) refractory to high-dose cytarabine (HDAC) based induction chemotherapy regimens. 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 participants 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 participants with PIF AML (% of patients who achieve

Clinical Details

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

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Overall Response (OR)

Treatment-Related Mortality (TRM)

Secondary outcome: Overall Survival (OS)

Detailed description: Salvage Chemotherapy Before Transplant: Study Drug Administration: On Days 1-5, participant will receive decitabine 1 time each day by vein over about 1-3 hours. On Days 6-10:

- Participant will receive cytarabine 1 time a day by vein over about 1-3 hours.

- On Days 6-8 only, participant will receive idarubicin 1 time a day by vein over about

30 minutes.

- On Days 6-9 only, participant will receive clofarabine 1 time a day by vein over about

1-2 hours. Study Visits: After participant's last study drug dose:

- Blood (about 2 teaspoons) will be drawn to check participant's kidney and liver

function.

- Participant will have an echocardiogram (ECHO) or multigated acquisition (MUGA) scan to

check their heart function.

- Participant will have a lung function test.

On Day 21 (+/- 7 days), participant will have a bone marrow biopsy/aspirate to check the status of the disease. To collect a bone marrow biopsy/aspirate, an area of the hip is numbed with anesthetic, and a small amount of bone and bone marrow is withdrawn through a large needle. If the results of participant's bone marrow biopsy/aspirate, blood tests, and heart and lung function tests show that they are eligible to receive an allogeneic stem cell transplant, they will be asked to sign a separate informed consent for the transplant. If the results of participant's bone marrow aspirate/biopsy, blood tests, and heart and lung function tests show that they are not eligible to receive an allogeneic stem cell transplant, they will not receive it. The study staff will call participant and ask how they are feeling and about any other drugs they may be taking every 3 months for 2 years after their last study drug dose. These calls should last about 5 minutes each. If participant is found to NOT be eligible to receive an allogeneic stem cell transplant, their doctor will discuss other treatment options with them. This is an investigational study. Decitabine is FDA approved and commercially available to treat myelodysplastic syndrome (MDS). Clofarabine is FDA approved and commercially available to treat ALL in children. Idarubicin and cytarabine are FDA approved and commercially available to treat AML. The study drug combination is investigational. Up to 75 participants will be enrolled in this study. All will take part at MD Anderson. Stem Cell Transplant: Study Drug Administration, Pharmacokinetic (PK) Testing, and Stem Cell Transplant: For a stem cell transplant, the days before participant receives their stem cells are called minus days. The day participant receives the stem cells is called Day 0. The days after participant receives the stem cells are called plus days.

On Day - 9, participant will be admitted to the hospital and given fluids by vein to hydrate

them.

On Day - 8, participant will receive a low-level "test" dose of busulfan by vein over about

45 minutes to 1 hour. Test doses are used to study how participant's body breaks down

busulfan and decide the dose of busulfan that they will receive on Days - 6 through -3.

Blood (about 1 teaspoon each time) will then be drawn for PK testing up to 11 times over the 11 hours after the busulfan test dose. PK testing measures the amount of study drug in the body at different time points. The study staff will tell participant more about the PK testing schedule. A heparin lock line will be placed in participant's vein before the PK testing to lower the number of needle sticks needed for these draws. If for any reason it is not possible for the PK tests to be performed, participant will receive the standard dose of busulfan.

On Day - 7, participant will rest.

On Days - 6 through -3, participant will receive fludarabine by vein over 1 hour, clofarabine

by vein over 1 hour, and then busulfan by vein over 3 hours.

On Days - 3 and -2, if participant will receive stem cells from a matched unrelated donor,

they will receive ATG by vein over 4 hours each day.

On Day - 2, if participant will receive stem cells from a haploidentical donor, they will

receive total body irradiation (TBI) one time. TBI involves the delivery of high doses of radiation designed to destroy cancer cells and/or lower the immune system in order to lower the risk of the body rejecting the new stem cells.

On Day - 2, participant will receive tacrolimus by vein over 24 hours every day until they

are able to take it by mouth. Tacrolimus is designed to weaken the immune system and lower

the risk of graft-versus-host-disease (GVHD - a reaction of the donor's immune cells against

participant's body). After participant is able to take tacrolimus by mouth, they will take it every day for about 6 months, or until the doctor thinks it is safe to stop.

On Day - 1, participant will rest. If participant will receive stem cells from a matched

sibling donor, they will rest on Days - 2 and -1.

On Day 0, participant will receive the donor's stem cells by vein. The infusion will last anywhere from about 30 minutes to several hours. If participant will receive stem cells from a haploidentical donor: After the stem cell infusion, participant will receive tacrolimus to help lower the risk of GVHD. Tacrolimus will be given by vein non-stop for about 2 weeks. After the 2 weeks of taking tacrolimus by vein, participant will take tacrolimus by mouth as a pill for at least 4 months after the transplant. On Days +3 and +4, participant will receive cyclophosphamide by vein over 3 hours. Cyclophosphamide is given to lower the immune system in order to lower the risk of GVHD. If participant receives stem cells from a matched sibling or matched unrelated donor: On Days +1, +3, +6, and +11, participant will receive methotrexate by vein over 30 minutes. Methotrexate is given to help prevent GVHD. Study Testing: Before participant is sent home from the hospital and/or clinic, they will receive additional written instructions. These instructions will include how often participant will come to the hospital/clinic, which standard drugs they will take at home, and what side effects they may have and what to do for them. After finishing the chemotherapy and transplant, participant's follow-up care will be routine standard of care follow-up that all patients receiving allogeneic stem cell transplantation receive. At each visit, participant will have a physical exam. Participant will be asked about any side effects they may have had. Blood (about 1 tablespoon) will be drawn for routine tests. If the doctor thinks it is needed, participant will have a bone marrow aspiration to check the status of the disease. To collect a bone marrow aspirate, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. Length of Treatment: After 2 years, patient's participation in this study will be over. Participant may be taken off study early if the disease gets worse, if their transplant does not "take" (graft failure), if they are unable to follow study directions, if their doctor thinks it is in their best interest, if the study is stopped, or if they choose to leave the study early. If for any reason participant wants to leave the study early, they must talk to the study doctor. It may be life-threatening to leave the study after participant has started to receive the study drugs but before they receive the stem cell transplant because their blood cell counts will be dangerously low. This is an investigational study. Decitabine is FDA approved and commercially available to treat myelodysplastic syndrome (MDS). Clofarabine is FDA approved and commercially available to treat ALL in children. Idarubicin and cytarabine are FDA approved and commercially available to treat AML. The study drug combination is investigational. Adding the transplant earlier in the course of leukemia treatment is investigational. Up to 75 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility

Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Patients age 18-60 years. 2. Patients with diagnosis of AML, judged primary refractory after up to 2 courses of induction with HDAC-based regimen (> 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 /= 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 of normal (x ULN) (3 x ULN if considered to be due to leukemic involvement or Gilbert's syndrome); c. Alanine aminotransferase (ALT) /= 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.

Locations and Contacts

Stefan Ciurea, MD, Phone: 713-792-8750

University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Not yet recruiting
Additional Information

University of Texas MD Anderson Cancer Center Website

Starting date: October 2015
Last updated: July 17, 2015

Page last updated: August 23, 2015

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