Allogeneic Stem Cell Transplant for CLL

Phase 1

Terminated

Conditions: Chronic Lymphocytic Leukemia
Prolymphocytic Leukemia
Allogeneic Hematopoietic Stem Cell Transplantation Recipient
Richter Syndrome

Interventions: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Biological: Anti-Thymocyte Globulin
Drug: Busulfan
Drug: Clofarabine
Biological: Filgrastim
Drug: Gemcitabine
Drug: Methotrexate
Drug: Tacrolimus

Registration Number: NCT01629511

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: This phase I/II trial studies the best dose and side effects of gemcitabine and how well it works with clofarabine and busulfan and donor stem cell transplant in treating participants with chronic lymphocytic leukemia. Drugs used in chemotherapy, such as gemcitabine, clofarabine, and busulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of gemcitabine when administered with busulfan and clofarabine.

II. To estimate the day 100 treatment-related mortality (TRM) for the preparative regimen busulfan, clofarabine, and gemcitabine followed by allogeneic hematopoietic cell transplantation (HCT) for patients with chronic lymphocytic leukemia (CLL).

SECONDARY OBJECTIVES:

I. To determine the rate of progression-free survival (PFS), graft versus host disease (GVHD), engraftment, and overall survival (OS) for this treatment regimen at one year post treatment completion.

OUTLINE: This is a dose-escalation study of gemcitabine.

Participants receive gemcitabine intravenously (IV) over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus orally (PO) daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim subcutaneously (SC) once daily (QD) beginning 1 week after transplant until blood cell levels return to normal.

After completion of study treatment, participants are followed up at 3, 6 and 12 months, then every 6 months for 1 year.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Patients with chronic lymphocytic leukemia, prolymphocytic leukemia, or Richter's transformation who are eligible for allogeneic transplantation and are not eligible for protocols of higher priority
A 10/10 HLA matched (high resolution typing at A, B, C, DRB1, DQ1) sibling or unrelated donor
Left ventricular ejection fraction (EF) > 40%
Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and corrected diffusion capacity of the lung for carbon monoxide (DLCO) > 40%
Serum creatinine < 1.6 mg/dL
Serum bilirubin < 2 X upper limit of normal
serum glutamate pyruvate transaminase (SGPT) < 2X upper limit of normal
Voluntary signed, written Institutional Review Board (IRB)-approved informed consent
Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study

Exclusion Criteria

Patient with active central nervous system (CNS) disease
Pregnant (positive beta human chorionic gonadotropin [HCG] test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding. Pregnancy testing is not required for post-menopausal or surgically sterilized women
Known infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)-I, hepatitis B, or hepatitis C
Active uncontrolled bacterial, viral or fungal infections
Patient has received other investigational drugs within 1 week before enrollment

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment (combination chemotherapy, stem cell transplant)	Anti-Thymocyte Globulin	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Allogeneic Hematopoietic Stem Cell Transplantation	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Filgrastim	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Clofarabine	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Busulfan	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Gemcitabine	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Tacrolimus	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.
Treatment (combination chemotherapy, stem cell transplant)	Methotrexate	Participants receive gemcitabine IV over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus PO daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim SC QD beginning 1 week after transplant until blood cell levels return to normal.

Primary Outcome Measures

Name	Time	Method
100 Day Treatment Related Mortality (TRM)	100 days post transplant	Number of deaths related to treatment by day 100 post allogeneic transplant
Maximum Tolerated Dose (MTD)	Enrollment up to day 30 post transplant	To find the maximum tolerated dose (MTD) of Gemcitabine when administered with Busulfan \& Clofarabine

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 1 year post transplant	Will be estimated by the method of Kaplan and Meier. Time-to-event distributions as function of patient baseline covariates will be evaluated using Bayesian time-to-event regression modeling.