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ATG + Plerixafor (AMD3100) + G-CSF (Filgrastim) + Fludarabine + Busulfan + Allogeneic blood stem cell transplant

ATG + MTD Plerixafor (AMD3100) + G-CSF (Filgrastim) + Fludarabine + Busulfan + Allogeneic blood stem cell transplant

Phase I: Starting dose of 0 (escalating doses 80, 160, 240 mcg/kg) given daily subcutaneously in abdomen for 4 doses.

Phase II: Maximum Tolerated Dose (MTD) as determined in Phase I

Dose of 10 mcg/kg subcutaneous injection beginning on day -9 daily for 6 days.

Filgrastim

Dose of 40 mg/m\^2 beginning on Day -6 for four consecutive days.

Dose of 130 mg/m\^2 for four consecutive days, immediately after completion of Fludarabine.

Allogeneic blood stem cell transplant

Dose(s) of 0.5 mg/kg on day -3; of 1.5 mg/kg on day -2; and of 2 mg/kg on day -1. Given only to patients with unrelated donors.

ATG (Thymoglobulin)

Marina Konopleva, MD, PhD

The goal of this clinical research study is to learn about the safety of AMD3100 (plerixafor) and G-CSF (filgrastim) in combination with fludarabine, busulfan, and an allogeneic blood stem cell transplant. This treatment will be studied in patients with acute myeloblastic leukemia (AML), myelodysplastic syndromes (MDS), or Chronic myelogenous leukemia (CML).

The Study Treatment:

Fludarabine is a chemotherapy drug that is designed to make cancer cells less able to repair damaged DNA (the genetic material of cells). This may increase the likelihood of the cells dying.

Busulfan is a chemotherapy drug that is designed to bind to DNA, which may cause cancer cells to die. It is commonly used in stem cell transplants.

Plerixafor and filgrastim are designed to cause cancer cells to move from the bone marrow into the blood stream. This may help to make the cancer cells more sensitive to being killed by the chemotherapy.

An "allogeneic" (from a donor) stem cell transplant is designed to help the recipient's body attack the cancer cells that may remain in the body after chemotherapy.

Study Groups and Plerixafor Dose Levels:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you joined this study. Up to 4 groups of 3 participants will be enrolled in the Phase I portion of the study, and up to 48 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of plerixafor you receive will depend on when you joined this study. The first group of participants will receive the lowest dose level of plerixafor. Each new group will receive a higher dose of plerixafor than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of plerixafor is found.

If you are enrolled in Phase II, you will receive plerixafor at the highest dose that was tolerated in the Phase I portion.

In this study, plerixafor is the only study drug where different dose levels are being tested and compared.

Drug Administration Before the Transplant:

You will receive your first dose of filgrastim on Day -9. (Day -9 means 9 days before the stem cell transplant, which will occur on Day 0).

Filgrastim is injected under the skin once a day from Day -9 through Day -4. Plerixafor is injected under the skin once a day from Day -7 through Day -4. The plerixafor injections will occur 8 hours before the fludarabine and busulfan chemotherapy.

The fludarabine and busulfan will be given by vein through a central venous catheter (CVC). A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

Fludarabine is given once a day from Day -6 through Day -3, over 1 hour each time. On these same days, busulfan will be given after the fludarabine, over 3 hours.

You will also receive tacrolimus in order to lower the risk of graft vs. host disease (GVHD). GVHD is a disease that occurs when the donor's immune cells react against the recipient's body, attacking the recipient's cells and tissues.

Starting on Day -2, tacrolimus will be given as a continuous (non-stop) infusion through the CVC. When the study doctor decides it seems safe, you will begin taking tacrolimus by mouth instead, for as long as the study doctor decides is necessary.

If your stem cell donor is not someone who is related to you, you will receive antithymocyte globulin (ATG) through the CVC once a day from Day -3 through Day -1. On Day -3, it will be given over at least 6 hours. On Days -2 and -1, it will be given over at least 4 hours. This drug is given in order to weaken your immune system in order to lower the risk of your immune system rejecting the transplanted cells.

Blood Tests Before the Transplant:

If you are in the Phase I part of this study, the following blood samples will be drawn and are not optional. Eight total blood samples (about 1 1/2 teaspoons each) will be drawn daily with your routine morning labs beginning before your first dose of study therapy (or Day -9) through Day -3. These samples will be used for research purposes, to study how the chemotherapy drugs and transplant may affect your normal cells and cancerous cells.

If you are in the Phase II part of the study the following blood samples are optional and if you agree, eight total blood samples (about 1 1/2 teaspoons each) will be drawn daily beginning before your first dose of study therapy (or Day -9) through Day -3. These samples will be used for research purposes, to study how the chemotherapy drugs and transplant may affect your normal cells and cancerous cells.

Stem Cell Transplant:

On Day 0, after 2 days of rest from chemotherapy, the donor's stem cells will be given to you by vein (through the CVC). This should take about 30-60 minutes.

Drug Administration After the Transplant:

In addition to continuing to receive tacrolimus to lower the risk of GVHD (as described above), after the transplant you will also receive methotrexate to lower the risk of GVHD. Methotrexate will be given by vein, through the CVC, over 15 minutes on Days 1, 3, and 6. It will also be given on Day 11 if your stem cell donor is someone who is not related to you.

Once a day, starting at 1 week after the transplant, you will receive filgrastim as an injection under your skin. These daily injections will continue until your blood counts recover.

Reasons for Stopping the Study Treatment Early:

If you experience intolerable side effects or the disease gets worse during study treatment, you will be taken off the study treatment.

Other Procedures After the Transplant:

You will remain in the hospital until your blood counts recover (usually about 4 weeks after the transplant). You will continue being monitored for any infections and transplant-related side effects for at least 100 days after the transplant.

At 1, 3, 6, and 12 months after the transplant, you will have blood tests (about 3 tablespoons) and bone marrow biopsies performed to check the status of the disease.

Length of Study Participation:

Your active participation in this study will be over at 12 months after the transplant. The study staff will continue to contact your local doctor regularly from then on. The purpose is to check the status of the disease and see how you are doing.

Up to 72 patients will take part in this study. All will be enrolled at The University of Texas (UT) MD Anderson.

Plerixafor and Granulocyte Colony-stimulating Factor (G-CSF) With Busulfan, Fludarabine and Thymoglobulin

G-CSF and Plerixafor With Busulfan and Fludarabine for Allogeneic Stem Cell Transplantation for Myeloid Leukemias

Phase I determination of MTD dose of Plerixafor in combination with a fixed dose of Filgrastim where dose limiting toxicity defined as any grade 4 non-hematologic toxicity observed within 28 days from Day 0 (day of transplant).

In Phase II portion of study, number of participants with treatment failure defined as either disease recurrence or death, measured from start of treatment to allo transplant at Day 0.

Number of participants with complete chimerism at day 30 where defined as: Engraftment: first day of three (3) consecutive days that Absolute neutrophil count (ANC) exceeds 0.5 X 109/L. Subsequent chimerism studies must demonstrate the presence of donor derived cells. Graft Failure: failure to achieve an ANC \>0.5 X 109/L for 3 consecutive days within 28 days after transplantation or a decline of ANC \<0.5 x 109/L for three consecutive days after initial documented engraftment unless this is correlated with progression / recurrence of the underlying malignancy.

Genzyme, a Sanofi Company

M.D. Anderson Cancer Center

ATG + Plerixafor (AMD3100) + G-CSF (Filgrastim) + Fludarabine + Busulfan + Allogeneic blood stem cell transplant:

Plerixafor (AMD3100) Starting dose of 0 (escalating doses 80, 160, 240 mcg/kg) given daily subcutaneously in abdomen for 4 doses + Thymoglobulin (ATG) 0.5 mg/kg on day -3; 1.5 mg/kg on day -2; \& 2 mg/kg on day -1. Given only to patients with unrelated donors + G-CSF (Filgrastim) 10 mcg/kg subcutaneous injection beginning on day -9 daily for 6 days + Fludarabine 40 mg/m\^2 beginning on Day -6 for four consecutive days + Busulfan 130 mg/m\^2 for four consecutive days, immediately after completion of Fludarabine + Allogeneic blood stem cell transplant of Stem Cell Infusion (Bone marrow or PBPC)

Phase I Plerixafor + G-CSF

Plerixafor Phase I Maximum Tolerated Dose (MTD) 240 mcg/kg daily for 4 days starting Day -7 + ATG 0.5 mg/kg day -3; 1.5 mg/kg on day -2; \& 2 mg/kg on day -1 only for participants with unrelated donors + G-CSF 10 mcg/kg subcutaneous injection beginning day -9 daily for 6 days + Fludarabine 40 mg/m\^2 beginning on Day -6 for four consecutive days + Busulfan 130 mg/m\^2 for 4 consecutive days, immediately after completion of Fludarabine + Allogeneic blood stem cell transplant.

Phase II Plerixafor 240 mcg/kg + G-CSF

Plerixafor (AMD3100) Starting dose of 0 (escalating doses 80, 160, 240 mcg/kg) given daily subcutaneously in abdomen for 4 doses + Thymoglobulin (ATG) 0.5 mg/kg on day -3; 1.5 mg/kg on day -2; \& 2 mg/kg on day -1. Given only to patients with unrelated donors + G-CSF (Filgrastim) 10 mcg/kg subcutaneous injection beginning on day -9 daily for 6 days + Fludarabine 40 mg/m\^2 beginning on Day -6 for four consecutive days + Busulfan 130 mg/m\^2 for four consecutive days, immediately after completion of Fludarabine + Allogeneic blood stem cell transplant of Stem Cell Infusion (Bone marrow or PBPC)

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Marina Konopleva, MD, PhD / Associate Professor

0 mcg/kg daily

80 mcg/kg daily

160 mcg/kg daily

240 mcg/kg daily

ATG + Plerixafor (AMD3100) + G-CSF (Filgrastim) + Fludarabine + Busulfan + Allogeneic blood stem cell transplant

Allogeneic blood stem cell transplant : Stem Cell Infusion (Bone marrow or PBPC)

Filgrastim : Dose of 10 mcg/kg subcutaneous injection beginning on day -9 daily for 6 days.

Fludarabine : Dose of 40 mg/m\^2 beginning on Day -6 for four consecutive days.

ATG (Thymoglobulin) : Dose(s) of 0.5 mg/kg on day -3; of 1.5 mg/kg on day -2; and of 2 mg/kg on day -1. Given only to patients with unrelated donors.

Busulfan : Dose of 130 mg/m\^2 for four consecutive days, immediately after completion of Fludarabine.

Plerixafor : Phase I: Starting dose of 0 (escalating doses 80, 160, 240 mcg/kg) given daily subcutaneously in abdomen for 4 doses.

Two participants of 18 registered left the study without receiving Plerixafor treatment and there were not available for MTD analysis.

Number of Participants With Grade 4 Dose Limiting Toxicity to Determine Maximum Tolerated Dose (MTD) Plerixafor

Participants in

Participants not in Complete Remission

Plerixafor escalating doses 0, 80, 160, 240 mcg/kg or MTD 240 mcg/kg given daily subcutaneously in abdomen for 4 doses + Thymoglobulin (ATG) 0.5 mg/kg on day -3; 1.5 mg/kg on day -2; \& 2 mg/kg on day -1. Given only to patients with unrelated donors + G-CSF (Filgrastim) 10 mcg/kg subcutaneous injection beginning on day -9 daily for 6 days + Fludarabine 40 mg/m\^2 beginning on Day -6 for four consecutive days + Busulfan 130 mg/m\^2 for four consecutive days, immediately after completion of Fludarabine + Allogeneic blood stem cell transplant of Stem Cell Infusion (Bone marrow or PBPC)

Overall Study: Plerixafor + G-CSF

Participants treated in the Phase 1 portion of the trial at the selected MTD dose were counted toward the maximum subgroup sample in Phase 2, therefore four of Phase I participants were included having received the MTD Plerixafor dose; however, one late participant in Phase 2 was not evaluable for the outcome.

Number of Participants Alive With no Disease Progression at Time of Allo Transplant

There were 39 participants receiving first transplants for acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) of both Phase I and Phase II who received MTD dose and allo transplant thus were evaluable for outcome.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Plerixafor and Granulocyte Colony-stimulating Factor (G-CSF) With Busulfan, Fludarabine and Thymoglobulin	NCT00822770	Stem Cell Trans... Leukemia	Plerixafor Filgrastim Fludarabine Busulfan Allogeneic bloo... ATG (Thymoglobu...	18 Years - 65 Years	M.D. Anderson Cancer Center
Plerixafor and Granulocyte Colony-stimulating Factor (G-CSF) With Busulfan, Fludarabine and Thymoglobulin	NCT00822770	Stem Cell Trans... Leukemia	Plerixafor Filgrastim Fludarabine Busulfan Allogeneic bloo... ATG (Thymoglobu...	18 Years - 65 Years	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for allogeneic blood stem cell transplant